Compounds and their methods of use

ABSTRACT

The present invention is directed to, in part, fused heteroaryl compounds and compositions useful for preventing and/or treating a disease or condition relating to aberrant function of a voltage-gated, sodium ion channel, for example, abnormal late/persistent sodium current. The fused heteroaryl compounds of the disclosure are represented by Formula (I): 
                         
wherein X, Y, Z, A, R 1  and R 2  are as defined in the specification. Methods of treating a disease or condition relating to aberrant function of a sodium ion channel including Dravet syndrome or epilepsy are also provided herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of, and priority to, U.S.Provisional Application No. 62/853,581, filed on May 28, 2019, thecontent of which is hereby incorporated by reference in its entirety.

BACKGROUND

Sodium ion (Na+) channels primarily open in a transient manner and arequickly inactivated, thereby generating a fast Na+ current to initiatethe action potential. The late or persistent sodium current (INaL) is asustained component of the fast Na+ current of cardiac myocytes andneurons. Many common neurological and cardiac conditions are associatedwith abnormal INaL enhancement, which contributes to the pathogenesis ofboth electrical and contractile dysfunction in mammals (see, e.g.,Pharmacol Ther (2008) 119:326-339). Accordingly, pharmaceuticalcompounds that selectively modulate sodium channel activity, e.g.,abnormal INaL, are useful in treating such disease states.

SUMMARY OF THE INVENTION

Described herein are fused heteroaryl compounds and compositions usefulfor preventing and/or treating a disease, disorder, or condition, e.g.,a disease, disorder, or condition relating to aberrant function of asodium ion channel, e.g., abnormal late sodium current (INaL).

In one aspect, the present disclosure features compounds of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; A is aryl or heteroaryl (e.g., 6-memberedaryl or heteroaryl), wherein aryl and heteroaryl are optionallysubstituted by one or more R³; R′ is hydrogen or alkyl; R¹ isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c); each R^(c) is independently hydrogen, alkyl,aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-a):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-b):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-c):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-d):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-e):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-f):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-g):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-h):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-i):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-j):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-k):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

In some embodiments, the compound of Formula (I) is a compound ofFormula (I-l):

or a pharmaceutically acceptable salt thereof, wherein the variables areas defined herein.

Other objects and advantages will become apparent to those skilled inthe art from a consideration of the ensuing Detailed Description,Examples, and Claims.

DETAILED DESCRIPTION OF THE INVENTION

As generally described herein, the present invention provides compoundsand compositions useful for preventing and/or treating a disease,disorder, or condition described herein, e.g., a disease, disorder, orcondition relating to aberrant function of a sodium ion channel, such asabnormal late sodium current (INaL). Exemplary diseases, disorders, orconditions include epilepsy or an epilepsy syndrome.

Definitions

Chemical Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. The chemical elements are identified inaccordance with the Periodic Table of the Elements, CAS version,Handbook of Chemistry and Physics, 75^(th) Ed., inside cover, andspecific functional groups are generally defined as described therein.Additionally, general principles of organic chemistry, as well asspecific functional moieties and reactivity, are described in ThomasSorrell, Organic Chemistry, University Science Books, Sausalito, 1999;Smith and March, March's Advanced Organic Chemistry, 5^(th) Edition,John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive OrganicTransformations, VCH Publishers, Inc., New York, 1989; and Carruthers,Some Modern Methods of Organic Synthesis, 3^(rd) Edition, CambridgeUniversity Press, Cambridge, 1987.

Compounds described herein can comprise one or more asymmetric centers,and thus can exist in various isomeric forms, e.g., enantiomers and/ordiastereomers. For example, the compounds described herein can be in theform of an individual enantiomer, diastereomer or geometric isomer, orcan be in the form of a mixture of stereoisomers, including racemicmixtures and mixtures enriched in one or more stereoisomer. Isomers canbe isolated from mixtures by methods known to those skilled in the art,including chiral high pressure liquid chromatography (HPLC) and theformation and crystallization of chiral salts; or preferred isomers canbe prepared by asymmetric syntheses. See, for example, Jacques et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistryof Carbon Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables ofResolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ.of Notre Dame Press, Notre Dame, Ind. 1972). The invention additionallyencompasses compounds described herein as individual isomerssubstantially free of other isomers, and alternatively, as mixtures ofvarious isomers.

As used herein a pure enantiomeric compound is substantially free fromother enantiomers or stereoisomers of the compound (i.e., inenantiomeric excess). In other words, an “S” form of the compound issubstantially free from the “R” form of the compound and is, thus, inenantiomeric excess of the “R” form. The term “enantiomerically pure” or“pure enantiomer” denotes that the compound comprises more than 75% byweight, more than 80% by weight, more than 85% by weight, more than 90%by weight, more than 91% by weight, more than 92% by weight, more than93% by weight, more than 94% by weight, more than 95% by weight, morethan 96% by weight, more than 97% by weight, more than 98% by weight,more than 98.5% by weight, more than 99% by weight, more than 99.2% byweight, more than 99.5% by weight, more than 99.6% by weight, more than99.7% by weight, more than 99.8% by weight or more than 99.9% by weight,of the enantiomer. In certain embodiments, the weights are based upontotal weight of all enantiomers or stereoisomers of the compound.

In the compositions provided herein, an enantiomerically pure compoundcan be present with other active or inactive ingredients. For example, apharmaceutical composition comprising enantiomerically pure R-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure R-compound. In certain embodiments, theenantiomerically pure R-compound in such compositions can, for example,comprise, at least about 95% by weight R-compound and at most about 5%by weight S-compound, by total weight of the compound. For example, apharmaceutical composition comprising enantiomerically pure S-compoundcan comprise, for example, about 90% excipient and about 10%enantiomerically pure S-compound. In certain embodiments, theenantiomerically pure S-compound in such compositions can, for example,comprise, at least about 95% by weight S-compound and at most about 5%by weight R-compound, by total weight of the compound. In certainembodiments, the active ingredient can be formulated with little or noexcipient or carrier.

Compound described herein may also comprise one or more isotopicsubstitutions. For example, H may be in any isotopic form, including ¹H,²H (D or deuterium), and ³H (T or tritium); C may be in any isotopicform, including ¹²C, ¹³C, and ¹⁴C; O may be in any isotopic form,including ¹⁶O and ¹⁸O; and the like.

The following terms are intended to have the meanings presentedtherewith below and are useful in understanding the description andintended scope of the present invention. When describing the invention,which may include compounds, pharmaceutical compositions containing suchcompounds and methods of using such compounds and compositions, thefollowing terms, if present, have the following meanings unlessotherwise indicated. It should also be understood that when describedherein any of the moieties defined forth below may be substituted with avariety of substituents, and that the respective definitions areintended to include such substituted moieties within their scope as setout below. Unless otherwise stated, the term “substituted” is to bedefined as set out below. It should be further understood that the terms“groups” and “radicals” can be considered interchangeable when usedherein. The articles “a” and “an” may be used herein to refer to one orto more than one (i.e. at least one) of the grammatical objects of thearticle. By way of example “an analogue” means one analogue or more thanone analogue.

When a range of values is listed, it is intended to encompass each valueand sub-range within the range. For example “C₁₋₆ alkyl” is intended toencompass, C₁, C₂, C₃, C₄, C₅, C₆, C₁₋₆, C₁₋₅, C₁₋₄, C₁₋₃, C₁₋₂, C₂₋₆,C₂₋₅, C₂₋₄, C₂₋₃, C₃₋₆, C₃₋₅, C₃₋₄, C₄₋₆, C₄₋₅, and C₅₋₆ alkyl.

“Alkyl” refers to a radical of a straight-chain or branched saturatedhydrocarbon group, e.g., having 1 to 20 carbon atoms (“C₁₋₂₀ alkyl”). Insome embodiments, an alkyl group has 1 to 10 carbon atoms (“C₁₋₁₀alkyl”). In some embodiments, an alkyl group has 1 to 9 carbon atoms(“C₁₋₉ alkyl”). In some embodiments, an alkyl group has 1 to 8 carbonatoms (“C₁₋₈ alkyl”). In some embodiments, an alkyl group has 1 to 7carbon atoms (“C₁₋₇ alkyl”). In some embodiments, an alkyl group has 1to 6 carbon atoms (“C₁₋₆ alkyl”). In some embodiments, an alkyl grouphas 1 to 5 carbon atoms (“C₁₋₅ alkyl”). In some embodiments, an alkylgroup has 1 to 4 carbon atoms (“C₁₋₄ alkyl”). In some embodiments, analkyl group has 1 to 3 carbon atoms (“C₁₋₃ alkyl”). In some embodiments,an alkyl group has 1 to 2 carbon atoms (“C₁₋₂ alkyl”). In someembodiments, an alkyl group has 1 carbon atom (“C₁ alkyl”). Examples ofC₁₋₆ alkyl groups include methyl, ethyl, propyl, isopropyl, butyl,isobutyl, pentyl, hexyl, and the like.

“Alkenyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon double bonds (e.g., 1, 2, 3, or 4 carbon-carbon doublebonds), and optionally one or more carbon-carbon triple bonds (e.g., 1,2, 3, or 4 carbon-carbon triple bonds) (“C₂₋₂₀ alkenyl”). In certainembodiments, alkenyl does not contain any triple bonds. In someembodiments, an alkenyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkenyl”). In some embodiments, an alkenyl group has 2 to 9 carbon atoms(“C₂₋₉ alkenyl”). In some embodiments, an alkenyl group has 2 to 8carbon atoms (“C₂₋₈ alkenyl”). In some embodiments, an alkenyl group has2 to 7 carbon atoms (“C₂₋₇ alkenyl”). In some embodiments, an alkenylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkenyl”). In some embodiments, analkenyl group has 2 to 5 carbon atoms (“C₂₋₅ alkenyl”). In someembodiments, an alkenyl group has 2 to 4 carbon atoms (“C₂₋₄ alkenyl”).In some embodiments, an alkenyl group has 2 to 3 carbon atoms (“C₂₋₃alkenyl”). In some embodiments, an alkenyl group has 2 carbon atoms (“C₂alkenyl”). The one or more carbon-carbon double bonds can be internal(such as in 2-butenyl) or terminal (such as in 1-butenyl). Examples ofC₂₋₄ alkenyl groups include ethenyl (C₂), 1-propenyl (C₃), 2-propenyl(C₃), 1-butenyl (C₄), 2-butenyl (C₄), butadienyl (C₄), and the like.Examples of C₂₋₆ alkenyl groups include the aforementioned C₂₋₄ alkenylgroups as well as pentenyl (C₅), pentadienyl (C₅), hexenyl (C₆), and thelike. Additional examples of alkenyl include heptenyl (C₇), octenyl(C₈), octatrienyl (C₈), and the like.

“Alkynyl” refers to a radical of a straight-chain or branchedhydrocarbon group having from 2 to 20 carbon atoms, one or morecarbon-carbon triple bonds (e.g., 1, 2, 3, or 4 carbon-carbon triplebonds), and optionally one or more carbon-carbon double bonds (e.g., 1,2, 3, or 4 carbon-carbon double bonds) (“C₂₋₂₀ alkynyl”). In certainembodiments, alkynyl does not contain any double bonds. In someembodiments, an alkynyl group has 2 to 10 carbon atoms (“C₂₋₁₀alkynyl”). In some embodiments, an alkynyl group has 2 to 9 carbon atoms(“C₂₋₉ alkynyl”). In some embodiments, an alkynyl group has 2 to 8carbon atoms (“C₂₋₈ alkynyl”). In some embodiments, an alkynyl group has2 to 7 carbon atoms (“C₂₋₇ alkynyl”). In some embodiments, an alkynylgroup has 2 to 6 carbon atoms (“C₂₋₆ alkynyl”). In some embodiments, analkynyl group has 2 to 5 carbon atoms (“C₂₋₅ alkynyl”). In someembodiments, an alkynyl group has 2 to 4 carbon atoms (“C₂₋₄ alkynyl”).In some embodiments, an alkynyl group has 2 to 3 carbon atoms (“C₂₋₃alkynyl”). In some embodiments, an alkynyl group has 2 carbon atoms (“C₂alkynyl”). The one or more carbon-carbon triple bonds can be internal(such as in 2-butynyl) or terminal (such as in 1-butynyl). Examples ofC₂₋₄ alkynyl groups include, without limitation, ethynyl (C₂),1-propynyl (C₃), 2-propynyl (C₃), 1-butynyl (C₄), 2-butynyl (C₄), andthe like. Examples of C₂₋₆ alkenyl groups include the aforementionedC₂₋₄ alkynyl groups as well as pentynyl (C₅), hexynyl (C₆), and thelike. Additional examples of alkynyl include heptynyl (C₇), octynyl(C₈), and the like.

As used herein, “alkylene,” “alkenylene,” and “alkynylene,” refer to adivalent radical of an alkyl, alkenyl, and alkynyl group respectively.When a range or number of carbons is provided for a particular“alkylene,” “alkenylene,” or “alkynylene,” group, it is understood thatthe range or number refers to the range or number of carbons in thelinear carbon divalent chain. “Alkylene,” “alkenylene,” and“alkynylene,” groups may be substituted or unsubstituted with one ormore substituents as described herein.

“Aryl” refers to a radical of a monocyclic or polycyclic (e.g., bicyclicor tricyclic) 4n+2 aromatic ring system (e.g., having 6, 10, or 14 πelectrons shared in a cyclic array) having 6-14 ring carbon atoms andzero heteroatoms provided in the aromatic ring system (“C₆₋₁₄ aryl”). Insome embodiments, an aryl group has six ring carbon atoms (“C₆ aryl”;e.g., phenyl). In some embodiments, an aryl group has ten ring carbonatoms (“C₁₀ aryl”; e.g., naphthyl such as 1-naphthyl and 2-naphthyl). Insome embodiments, an aryl group has fourteen ring carbon atoms (“C₁₄aryl”; e.g., anthracyl). “Aryl” also includes ring systems wherein thearyl ring, as defined above, is fused with one or more carbocyclyl orheterocyclyl groups wherein the radical or point of attachment is on thearyl ring, and in such instances, the number of carbon atoms continue todesignate the number of carbon atoms in the aryl ring system. Typicalaryl groups include, but are not limited to, groups derived fromaceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene,benzene, chrysene, coronene, fluoranthene, fluorene, hexacene,hexaphene, hexalene, as-indacene, s-indacene, indane, indene,naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene,pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene,picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, andtrinaphthalene. Particularly aryl groups include phenyl, naphthyl,indenyl, and tetrahydronaphthyl.

“Fused aryl” refers to an aryl having two of its ring carbon in commonwith a second aryl or heteroaryl ring or with a carbocyclyl orheterocyclyl ring.

“Heteroaryl” refers to a radical of a 5-10 membered monocyclic orbicyclic 4n+2 aromatic ring system (e.g., having 6 or 10 π electronsshared in a cyclic array) having ring carbon atoms and 1-4 ringheteroatoms provided in the aromatic ring system, wherein eachheteroatom is independently selected from nitrogen, oxygen and sulfur(“5-10 membered heteroaryl”). In heteroaryl groups that contain one ormore nitrogen atoms, the point of attachment can be a carbon or nitrogenatom, as valency permits. Heteroaryl bicyclic ring systems can includeone or more heteroatoms in one or both rings. “Heteroaryl” includes ringsystems wherein the heteroaryl ring, as defined above, is fused with oneor more carbocyclyl or heterocyclyl groups wherein the point ofattachment is on the heteroaryl ring, and in such instances, the numberof ring members continue to designate the number of ring members in theheteroaryl ring system. “Heteroaryl” also includes ring systems whereinthe heteroaryl ring, as defined above, is fused with one or more arylgroups wherein the point of attachment is either on the aryl orheteroaryl ring, and in such instances, the number of ring membersdesignates the number of ring members in the fused (aryl/heteroaryl)ring system. Bicyclic heteroaryl groups wherein one ring does notcontain a heteroatom (e.g., indolyl, quinolinyl, carbazolyl, and thelike) the point of attachment can be on either ring, i.e., either thering bearing a heteroatom (e.g., 2-indolyl) or the ring that does notcontain a heteroatom (e.g., 5-indolyl).

In some embodiments, a heteroaryl group is a 5-10 membered aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-10 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-8 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-8 membered heteroaryl”). In someembodiments, a heteroaryl group is a 5-6 membered aromatic ring systemhaving ring carbon atoms and 1-4 ring heteroatoms provided in thearomatic ring system, wherein each heteroatom is independently selectedfrom nitrogen, oxygen, and sulfur (“5-6 membered heteroaryl”). In someembodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatomsselected from nitrogen, oxygen, and sulfur. In some embodiments, the 5-6membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen,oxygen, and sulfur. In some embodiments, the 5-6 membered heteroaryl has1 ring heteroatom selected from nitrogen, oxygen, and sulfur.

Exemplary 5-membered heteroaryl groups containing one heteroatominclude, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary5-membered heteroaryl groups containing two heteroatoms include, withoutlimitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, andisothiazolyl. Exemplary 5-membered heteroaryl groups containing threeheteroatoms include, without limitation, triazolyl, oxadiazolyl, andthiadiazolyl. Exemplary 5-membered heteroaryl groups containing fourheteroatoms include, without limitation, tetrazolyl. Exemplary6-membered heteroaryl groups containing one heteroatom include, withoutlimitation, pyridinyl. Exemplary 6-membered heteroaryl groups containingtwo heteroatoms include, without limitation, pyridazinyl, pyrimidinyl,and pyrazinyl. Exemplary 6-membered heteroaryl groups containing threeor four heteroatoms include, without limitation, triazinyl andtetrazinyl, respectively. Exemplary 7-membered heteroaryl groupscontaining one heteroatom include, without limitation, azepinyl,oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groupsinclude, without limitation, indolyl, isoindolyl, indazolyl,benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl,benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl,benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl,indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groupsinclude, without limitation, naphthyridinyl, pteridinyl, quinolinyl,isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

Examples of representative heteroaryls include the following:

wherein each Z is selected from carbonyl, N, NR⁶⁵, O, and S; and R⁶⁵ isindependently hydrogen, C₁-C₈ alkyl, C₃-C₁₀ carbocyclyl, 4-10 memberedheterocyclyl, C₆-C₁₀ aryl, and 5-10 membered heteroaryl.

“Carbocyclyl” or “carbocyclic” refers to a radical of a non-aromaticcyclic hydrocarbon group having from 3 to 10 ring carbon atoms (“C₃₋₁₀carbocyclyl”) and zero heteroatoms in the non-aromatic ring system. Insome embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms(“C₃₋₈ carbocyclyl”). In some embodiments, a carbocyclyl group has 3 to6 ring carbon atoms (“C₃₋₆ carbocyclyl”). In some embodiments, acarbocyclyl group has 3 to 6 ring carbon atoms (“C₃₋₆ carbocyclyl”). Insome embodiments, a carbocyclyl group has 5 to 10 ring carbon atoms(“C₅₋₁₀ carbocyclyl”). Exemplary C₃₋₆ carbocyclyl groups include,without limitation, cyclopropyl (C₃), cyclopropenyl (C₃), cyclobutyl(C₄), cyclobutenyl (C₄), cyclopentyl (C₅), cyclopentenyl (C₅),cyclohexyl (C₆), cyclohexenyl (C₆), cyclohexadienyl (C₆), and the like.Exemplary C₃₋₈ carbocyclyl groups include, without limitation, theaforementioned C₃₋₆ carbocyclyl groups as well as cycloheptyl (C₇),cycloheptenyl (C₇), cycloheptadienyl (C₇), cycloheptatrienyl (C₇),cyclooctyl (C₈), cyclooctenyl (C₈), bicyclo[2.2.1]heptanyl (C₇),bicyclo[2.2.2]octanyl (C₈), and the like. Exemplary C₃₋₁₀ carbocyclylgroups include, without limitation, the aforementioned C₃₋₈ carbocyclylgroups as well as cyclononyl (C₉), cyclononenyl (C₉), cyclodecyl (C₁₀),cyclodecenyl (C₁₀), octahydro-1H-indenyl (C₉), decahydronaphthalenyl(C₁₀), spiro[4.5]decanyl (C₁₀), and the like. As the foregoing examplesillustrate, in certain embodiments, the carbocyclyl group is eithermonocyclic (“monocyclic carbocyclyl”) or contain a fused, bridged orspiro ring system such as a bicyclic system (“bicyclic carbocyclyl”) andcan be saturated or can be partially unsaturated. “Carbocyclyl” alsoincludes ring systems wherein the carbocyclyl ring, as defined above, isfused with one or more aryl or heteroaryl groups wherein the point ofattachment is on the carbocyclyl ring, and in such instances, the numberof carbons continue to designate the number of carbons in thecarbocyclic ring system.

“Heterocyclyl” or “heterocyclic” refers to a radical of a 3- to10-membered non-aromatic ring system having ring carbon atoms and 1 to 4ring heteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“3-10 memberedheterocyclyl”). In heterocyclyl groups that contain one or more nitrogenatoms, the point of attachment can be a carbon or nitrogen atom, asvalency permits. A heterocyclyl group can either be monocyclic(“monocyclic heterocyclyl”) or a fused, bridged or spiro ring systemsuch as a bicyclic system (“bicyclic heterocyclyl”), and can besaturated or can be partially unsaturated. Heterocyclyl bicyclic ringsystems can include one or more heteroatoms in one or both rings.“Heterocyclyl” also includes ring systems wherein the heterocyclyl ring,as defined above, is fused with one or more carbocyclyl groups whereinthe point of attachment is either on the carbocyclyl or heterocyclylring, or ring systems wherein the heterocyclyl ring, as defined above,is fused with one or more aryl or heteroaryl groups, wherein the pointof attachment is on the heterocyclyl ring, and in such instances, thenumber of ring members continue to designate the number of ring membersin the heterocyclyl ring system.

In some embodiments, a heterocyclyl group is a 5-10 memberednon-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, sulfur, boron, phosphorus, and silicon (“5-10 memberedheterocyclyl”). In some embodiments, a heterocyclyl group is a 5-8membered non-aromatic ring system having ring carbon atoms and 1-4 ringheteroatoms, wherein each heteroatom is independently selected fromnitrogen, oxygen, and sulfur (“5-8 membered heterocyclyl”). In someembodiments, a heterocyclyl group is a 5-6 membered non-aromatic ringsystem having ring carbon atoms and 1-4 ring heteroatoms, wherein eachheteroatom is independently selected from nitrogen, oxygen, and sulfur(“5-6 membered heterocyclyl”). In some embodiments, the 5-6 memberedheterocyclyl has 1-3 ring heteroatoms selected from nitrogen, oxygen,and sulfur. In some embodiments, the 5-6 membered heterocyclyl has 1-2ring heteroatoms selected from nitrogen, oxygen, and sulfur. In someembodiments, the 5-6 membered heterocyclyl has one ring heteroatomselected from nitrogen, oxygen, and sulfur.

Exemplary 3-membered heterocyclyl groups containing one heteroatominclude, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary4-membered heterocyclyl groups containing one heteroatom include,without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary5-membered heterocyclyl groups containing one heteroatom include,without limitation, tetrahydrofuranyl, dihydrofuranyl,tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyland pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groupscontaining two heteroatoms include, without limitation, dioxolanyl,oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-memberedheterocyclyl groups containing three heteroatoms include, withoutlimitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary6-membered heterocyclyl groups containing one heteroatom include,without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl,and thianyl. Exemplary 6-membered heterocyclyl groups containing twoheteroatoms include, without limitation, piperazinyl, morpholinyl,dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containingtwo heteroatoms include, without limitation, triazinanyl. Exemplary7-membered heterocyclyl groups containing one heteroatom include,without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary8-membered heterocyclyl groups containing one heteroatom include,without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary5-membered heterocyclyl groups fused to a C₆ aryl ring (also referred toherein as a 5,6-bicyclic heterocyclic ring) include, without limitation,indolinyl, isoindolinyl, dihydrobenzofuranyl, dihydrobenzothienyl,benzoxazolinonyl, and the like. Exemplary 6-membered heterocyclyl groupsfused to an aryl ring (also referred to herein as a 6,6-bicyclicheterocyclic ring) include, without limitation, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

“Hetero” when used to describe a compound or a group present on acompound means that one or more carbon atoms in the compound or grouphave been replaced by a nitrogen, oxygen, or sulfur heteroatom. Heteromay be applied to any of the hydrocarbyl groups described above such asalkyl, e.g., heteroalkyl, carbocyclyl, e.g., heterocyclyl, aryl, e.g.,heteroaryl, cycloalkenyl, e.g., cycloheteroalkenyl, and the like havingfrom 1 to 5, and particularly from 1 to 3 heteroatoms.

“Cyano” refers to the radical —CN.

“Halo” or “halogen” refers to fluoro (F), chloro (Cl), bromo (Br), andiodo (I). In certain embodiments, the halo group is either fluoro orchloro.

“Haloalkyl” refers to an alkyl group substituted with one or morehalogen atoms.

“Nitro” refers to the radical —NO₂.

In general, the term “substituted”, whether preceded by the term“optionally” or not, means that at least one hydrogen present on a group(e.g., a carbon or nitrogen atom) is replaced with a permissiblesubstituent, e.g., a substituent which upon substitution results in astable compound, e.g., a compound which does not spontaneously undergotransformation such as by rearrangement, cyclization, elimination, orother reaction. Unless otherwise indicated, a “substituted” group has asubstituent at one or more substitutable positions of the group, andwhen more than one position in any given structure is substituted, thesubstituent is either the same or different at each position.

A “counterion” or “anionic counterion” is a negatively charged groupassociated with a cationic quaternary amino group in order to maintainelectronic neutrality. Exemplary counterions include halide ions (e.g.,F⁻, Cl⁻, Br⁻, I⁻), NO₃ ⁻, ClO₄ ⁻, OH⁻, H₂PO₄ ⁻, HSO₄ ⁻, SO₄ ⁻² sulfonateions (e.g., methansulfonate, trifluoromethanesulfonate,p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,ethan-1-sulfonic acid-2-sulfonate, and the like), and carboxylate ions(e.g., acetate, ethanoate, propanoate, benzoate, glycerate, lactate,tartrate, glycolate, and the like).

Nitrogen atoms can be substituted or unsubstituted as valency permits,and include primary, secondary, tertiary, and quarternary nitrogenatoms. Exemplary nitrogen atom substitutents include, but are notlimited to, hydrogen, —OH, —OR^(aa), —N(R^(cc))₂, —CN, —C(═O)R^(aa),—C(═O)N(R^(cc))₂, —CO₂R^(aa), —SO₂R^(aa), —C(═NR^(bb))R^(aa)—,—C(═NR^(cc))OR^(aa), —C(═NR^(cc))N(R^(cc))₂, —SO₂N(R^(cc))₂, —SO₂R^(cc),—SO₂OR^(cc), —SOR^(aa), —C(═S)N(R^(cc))₂, —C(═O)SR^(cc), —C(═S)SR^(cc),—P(═O)₂R^(aa), —P(═O)(R^(aa))₂, —P(═O)₂N(R^(cc))₂, —P(═O)(NR^(cc))₂,C₁₋₁₀ alkyl, C₁₋₁₀ perhaloalkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₁₀carbocyclyl, 3-14 membered heterocyclyl, C₆₋₁₄ aryl, and 5-14 memberedheteroaryl, or two R^(cc) groups attached to a nitrogen atom are joinedto form a 3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,and heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5R^(dd) groups, and wherein R^(aa), R^(bb), R^(cc) and R^(dd) are asdefined above.

These and other exemplary substituents are described in more detail inthe Detailed Description, Examples, and Claims. The invention is notintended to be limited in any manner by the above exemplary listing ofsubstituents.

Other Definitions

The term “pharmaceutically acceptable salt” refers to those salts whichare, within the scope of sound medical judgment, suitable for use incontact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. Pharmaceuticallyacceptable salts are well known in the art. For example, Berge et al.,describes pharmaceutically acceptable salts in detail in J.Pharmaceutical Sciences (1977) 66:1-19. Pharmaceutically acceptablesalts of the compounds of this invention include those derived fromsuitable inorganic and organic acids and bases. Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloric acid,hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid orwith organic acids such as acetic acid, oxalic acid, maleic acid,tartaric acid, citric acid, succinic acid or malonic acid or by usingother methods used in the art such as ion exchange. Otherpharmaceutically acceptable salts include adipate, alginate, ascorbate,aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,camphorate, camphorsulfonate, citrate, cyclopentanepropionate,digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate,hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate,lactate, laurate, lauryl sulfate, malate, maleate, malonate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate,oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate,phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate,tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts,and the like. Pharmaceutically acceptable salts derived from appropriatebases include alkali metal, alkaline earth metal, ammonium andN⁺(C₁₋₄alkyl)₄ salts. Representative alkali or alkaline earth metalsalts include sodium, lithium, potassium, calcium, magnesium, and thelike. Further pharmaceutically acceptable salts include, whenappropriate, nontoxic ammonium, quaternary ammonium, and amine cationsformed using counterions such as halide, hydroxide, carboxylate,sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

A “subject” to which administration is contemplated includes, but is notlimited to, humans (i.e., a male or female of any age group, e.g., apediatric subject (e.g, infant, child, adolescent) or adult subject(e.g., young adult, middle-aged adult or senior adult)) and/or anon-human animal, e.g., a mammal such as primates (e.g., cynomolgusmonkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents,cats, and/or dogs. In certain embodiments, the subject is a human. Incertain embodiments, the subject is a non-human animal. The terms“human,” “patient,” and “subject” are used interchangeably herein.

Disease, disorder, and condition are used interchangeably herein.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while asubject is suffering from the specified disease, disorder or condition,which reduces the severity of the disease, disorder or condition, orretards or slows the progression of the disease, disorder or condition(“therapeutic treatment”).

In general, the “effective amount” of a compound refers to an amountsufficient to elicit the desired biological response. As will beappreciated by those of ordinary skill in this art, the effective amountof a compound of the invention may vary depending on such factors as thedesired biological endpoint, the pharmacokinetics of the compound, thedisease being treated, the mode of administration, and the age, health,and condition of the subject. An effective amount encompassestherapeutic and prophylactic treatment.

As used herein, and unless otherwise specified, a “therapeuticallyeffective amount” of a compound is an amount sufficient to provide atherapeutic benefit in the treatment of a disease, disorder orcondition, or to delay or minimize one or more symptoms associated withthe disease, disorder or condition. A therapeutically effective amountof a compound means an amount of therapeutic agent, alone or incombination with other therapies, which provides a therapeutic benefitin the treatment of the disease, disorder or condition. The term“therapeutically effective amount” can encompass an amount that improvesoverall therapy, reduces or avoids symptoms or causes of disease orcondition, or enhances the therapeutic efficacy of another therapeuticagent.

In an alternate embodiment, the present invention contemplatesadministration of the compounds of the present invention or apharmaceutically acceptable salt or a pharmaceutically acceptablecomposition thereof, as a prophylactic before a subject begins to sufferfrom the specified disease, disorder or condition. As used herein,“prophylactic treatment,” “preventive treatment,” “prevent,”“preventing” or “prevention” contemplates an action that occurs before asubject begins to suffer from the specified disease, disorder orcondition. In some embodiments, the terms encompass the inhibition orreduction of the seriousness, progression, or recurrence of a symptom ofthe particular disease, disorder or condition. In some embodiments,patients with familial history of a disease, disorder or conditiondescribed herein or with a history of recurring symptoms are potentialcandidates for the prevention. As used herein, and unless otherwisespecified, a “prophylactically effective amount” of a compound is anamount sufficient to prevent a disease, disorder or condition, or one ormore symptoms associated with the disease, disorder or condition, orprevent its recurrence. A prophylactically effective amount of acompound means an amount of a therapeutic agent, alone or in combinationwith other agents, which provides a prophylactic benefit in theprevention of the disease, disorder or condition. The term“prophylactically effective amount” can encompass an amount thatimproves overall prophylaxis or enhances the prophylactic efficacy ofanother prophylactic agent.

Compounds

In one aspect, the present invention features a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; A is aryl or heteroaryl (e.g., 6-memberedaryl or heteroaryl), wherein aryl and heteroaryl are optionallysubstituted by one or more R³; R′ is hydrogen or alkyl; R¹ isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c); each R^(c) is independently hydrogen, alkyl,aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.

In some embodiments, X is CR′. In some embodiments, R′ is hydrogen.

In some embodiments, X is N. In some embodiments, X is N and Y and Z areeach independently CR′ (e.g., CH).

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl is substituted by1 R³. In some embodiments, A is phenyl is substituted by 1 R³ in thepara position.

In some embodiments, R³ is —OR^(c). In some embodiments, R^(c) is alkyl.In some embodiments, R is alkyl substituted by one or more R⁶. In someembodiments, R⁶ is halo. In some embodiments, R³-R⁶ is —OCF₃.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is alkyl.In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ is alkyl(e.g., C₁₋₆ alkyl) substituted with 1-4 R⁴. In some embodiments, R⁴ ishalo (e.g., fluoro). In some embodiments, R¹ is —CF₃.

In some embodiments, R² is hydrogen. In some embodiments, R¹ is alkyland R² is hydrogen. In some embodiments, R¹ is —CF₃ and R² is hydrogen.

In another aspect, provided is a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is N or CR′; R′ is hydrogen or alkyl; R¹ is hydrogen, alkyl,carbocyclyl, or heterocyclyl, wherein alkyl, carbocyclyl, andheterocyclyl are optionally substituted with one or more R⁴; each R³ isindependently alkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or—OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁵; each of R⁴ and R⁵ is independentlyalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro,or —OR; each R^(c) is independently hydrogen, alkyl, aryl, carbocyclyl,heterocyclyl, or heteroaryl, wherein alkyl, aryl, or heteroaryl isoptionally substituted by one or more R⁶; each R^(d) is independentlyhydrogen or alkyl; each R⁶ is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl is optionallysubstituted with one or more halo; and n is 1, 2, 3, 4, or 5.

In another aspect, provided is a compound of Formula (I-b):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is N or CR²; R¹ is hydrogen, alkyl, carbocyclyl, or heterocyclyl,wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁴; R² is hydrogen or alkyl; each R³ is independentlyalkyl, carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OR^(c),wherein alkyl, carbocyclyl, and heterocyclyl are optionally substitutedwith one or more R⁵; each of R⁴ and R⁵ is independently alkyl,carbocyclyl, heterocyclyl, aryl, heteroaryl, halo, cyano, nitro, or—OR^(c); each R^(c) is independently hydrogen, alkyl, aryl, carbocyclyl,heterocyclyl, or heteroaryl, wherein alkyl, aryl, or heteroaryl isoptionally substituted by one or more R⁶; each R^(d) is independentlyhydrogen or alkyl; each R⁶ is independently alkyl, carbocyclyl,heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl is optionallysubstituted with one or more halo; and m is 0, 1, 2, or 3.

In some embodiments, X is CR′. In some embodiments, R′ is hydrogen.

In some embodiments, X is N.

In some embodiments, A is aryl. In some embodiments, A is 6-memberedaryl (e.g., phenyl). In some embodiments, A is phenyl is substituted by1 R³. In some embodiments, A is phenyl is substituted by 1 R³ in thepara position.

In some embodiments, R³ is —OR^(c). In some embodiments, R^(c) is alkyl.In some embodiments, R is alkyl substituted by one or more R⁶. In someembodiments, R⁶ is halo. In some embodiments, R³ is —OCF₃.

In some embodiments, R¹ is hydrogen. In some embodiments, R¹ is alkyl.In some embodiments, R¹ is C₁₋₆ alkyl. In some embodiments, R¹ is alkyl(e.g., C₁₋₆ alkyl) substituted with 1-4 R⁴. In some embodiments, R⁴ ishalo (e.g., fluoro). In some embodiments, R¹ is —CF₃.

In some embodiments, X, Y, and Z are CH.

In some embodiments, X is N, Y and Z are CH.

In some embodiments, X and Y are CH, Z is N.

In some embodiments, X and Z are CH, Y is N.

In some embodiments, R¹ is hydrogen or alkyl optionally substituted withone or more halogen.

In some embodiments, R¹ is hydrogen, —CF₃, or —CHF₂.

In some embodiments, each R³ is —OR^(c), alkyl, or halo.

In some embodiments, the compound of Formula (I) is a compound offormula (I-c):

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3,or 4, and R¹, X, Y, Z, R^(c), and R³ are as defined in formula (I-a).

In some embodiments, the compound of Formula (I) is a compound offormula (I-d):

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3,or 4, and R¹, R^(c), and R³ are as defined in formula (I-a).

In some embodiments, the compound of Formula (I) is a compound offormula (I-e):

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3,or 4, and R¹, R^(c), and R³ are as defined in formula (I-a).

In some embodiments, the compound of Formula (I) is a compound offormula (I-f):

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3,or 4, and R¹, R^(c), and R³ are as defined in formula (I-a).

In some embodiments, the compound of Formula (I) is a compound offormula (I-g):

or a pharmaceutically acceptable salt thereof, wherein: m is 0, 1, 2, 3,or 4, and R¹, R^(c), and R³ are as defined in formula (I-a).

In some embodiments, the compound of Formula (I) is a compound offormula (I-h):

or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, 2, or3, and R¹, X, Y, Z, R^(c), and R³ are as defined in formula (I-b). Insome embodiments, the compound of Formula (I) is a compound of formula(I-i):

or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, 2, or3, and R¹, R^(c), and R³ are as defined in formula (I-b).

In some embodiments, the compound of Formula (I) is a compound offormula (I-j):

or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, 2, or3, and R¹, R^(c), and R³ are as defined in formula (I-b).

In some embodiments, the compound of Formula (I) is a compound offormula (I-k):

or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, 2, or3, and R¹, R^(c), and R³ are as defined in formula (I-b).

In some embodiments, the compound of Formula (I) is a compound offormula (I-l):

or a pharmaceutically acceptable salt thereof, wherein: p is 0, 1, 2, or3, and R¹, R^(c), and R³ are as defined in formula (I-b).

In any and all aspects, in some embodiments, the compound of Formulas(I) and (I-a) is selected from:

or a pharmaceutically acceptable salt thereof.Methods of Treatment

Compounds and compositions described herein are generally useful for themodulating the activity of sodium channels and are useful in treatingconditions relating to aberrant function of a sodium channel ionchannel, e.g., abnormal late sodium (INaL) current. In some embodiments,a compound provided by the present invention is effective in thetreatment of epilepsy or an epilepsy syndrome, a neurodevelopmentaldisorder, pain, or a neuromuscular disorder. A provided compound,pharmaceutically acceptable salt thereof, or composition may alsomodulate all sodium ion channels, or may be specific to only one or aplurality of sodium ion channels, e.g., Nav 1.1, 1.2, 1.3, 1.4, 1.5,1.6, 1.7, 1.8, and/or 1.9.

In typical embodiments, the present invention is intended to encompassthe compounds disclosed herein, and the pharmaceutically acceptablesalts, pharmaceutically acceptable esters, tautomeric forms, polymorphs,and prodrugs of such compounds. In some embodiments, the presentinvention includes a pharmaceutically acceptable addition salt, apharmaceutically acceptable ester, a solvate (e.g., hydrate) of anaddition salt, a tautomeric form, a polymorph, an enantiomer, a mixtureof enantiomers, a stereoisomer or mixture of stereoisomers (pure or as aracemic or non-racemic mixture) of a compound described herein, e.g. acompound of Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f),(I-g), (I-h), (I-i), (I-j), (I-k), or (I-l); such as a compound ofFormula (I) named herein.

Epilepsy and Epilepsy Syndromes

The compounds described herein are useful in the treatment of epilepsyand epilepsy syndromes. Epilepsy is a CNS disorder in which nerve cellactivity in the brain becomes disrupted, causing seizures or periods ofunusual behavior, sensations and sometimes loss of consciousness.Seizure symptoms will vary widely, from a simple blank stare for a fewseconds to repeated twitching of their arms or legs during a seizure.

Epilepsy may involve a generalized seizure or a partial or focalseizure. All areas of the brain are involved in a generalized seizure. Aperson experiencing a generalized seizure may cry out or make somesound, stiffen for several seconds to a minute a then have rhythmicmovements of the arms and legs. The eyes are generally open, the personmay appear not to be breathing and may actually turn blue. The return toconsciousness is gradual and the person maybe confused from minutes tohours. There are six main types of generalized seizures: tonic-clonic,tonic, clonic, myoclonic, absence, and atonic seizures. In a partial orfocal seizure, only part of the brain is involved, so only part of thebody is affected. Depending on the part of the brain having abnormalelectrical activity, symptoms may vary.

Epilepsy, as described herein, includes a generalized, partial, complexpartial, tonic clonic, clonic, tonic, refractory seizures, statusepilepticus, absence seizures, febrile seizures, or temporal lobeepilepsy.

The compounds described herein (e.g. a compound of Formula (I), (I-a),(I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), or(I-l)) may also be useful in the treatment of epilepsy syndromes. Severesyndromes with diffuse brain dysfunction caused, at least partly, bysome aspect of epilepsy, are also referred to as epilepticencephalopathies. These are associated with frequent seizures that areresistant to treatment and severe cognitive dysfunction, for instanceWest syndrome.

In some embodiments, the epilepsy syndrome comprises an epilepticencephalopathy, such as Dravet syndrome, Angelman syndrome, CDKL5disorder, frontal lobe epilepsy, infantile spasms, West's syndrome,Juvenile Myoclonic Epilepsy, Landau-Kleffner syndrome, Lennox-Gastautsyndrome, Ohtahara syndrome, PCDH19 epilepsy, or Glut1 deficiency.

In some embodiments, the epilepsy or epilepsy syndrome is a geneticepilepsy or a genetic epilepsy syndrome. In some embodiments, epilepsyor an epilepsy syndrome comprises epileptic encephalopathy, epilepticencephalopathy with SCN1A, SCN2A, SCN8A mutations, early infantileepileptic encephalopathy, Dravet syndrome, Dravet syndrome with SCN1Amutation, generalized epilepsy with febrile seizures, intractablechildhood epilepsy with generalized tonic-clonic seizures, infantilespasms, benign familial neonatal-infantile seizures, SCN2A epilepticencephalopathy, focal epilepsy with SCN3A mutation, cryptogenicpediatric partial epilepsy with SCN3A mutation, SCN8A epilepticencephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden unexpected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy.

In some embodiments, the methods described herein further compriseidentifying a subject having epilepsy or an epilepsy syndrome (e.g.,epileptic encephalopathy, epileptic encephalopathy with SCN1A, SCN2A,SCN8A mutations, early infantile epileptic encephalopathy, Dravetsyndrome, Dravet syndrome with SCN1A mutation, generalized Epilepsy withfebrile seizures, intractable childhood epilepsy with generalizedtonic-clonic seizures, infantile spasms, benign familialneonatal-infantile seizures, SCN2A epileptic encephalopathy, focalepilepsy with SCN3A mutation, cryptogenic pediatric partial epilepsywith SCN3A mutation, SCN8A epileptic encephalopathy, sudden unexpecteddeath in epilepsy, Rasmussen encephalitis, malignant migrating partialseizures of infancy, autosomal dominant nocturnal frontal lobe epilepsy,sudden unexpected death in epilepsy (SUDEP), KCNQ2 epilepticencephalopathy, or KCNT1 epileptic encephalopathy) prior toadministration of a compound described herein (e.g., a compound ofFormula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h),(I-i), (I-j), (I-k), or (I-l)).

In one aspect, the present invention features a method of treatingepilepsy or an epilepsy syndrome (e.g., epileptic encephalopathy,epileptic encephalopathy with SCN1A, SCN2A, SCN8A mutations, earlyinfantile epileptic encephalopathy, Dravet syndrome, Dravet syndromewith SCN1A mutation, generalized Epilepsy with febrile seizures,intractable childhood epilepsy with generalized tonic-clonic seizures,infantile spasms, benign familial neonatal-infantile seizures, SCN2Aepileptic encephalopathy, focal epilepsy with SCN3A mutation,cryptogenic pediatric partial epilepsy with SCN3A mutation, SCN8Aepileptic encephalopathy, sudden unexpected death in epilepsy, Rasmussenencephalitis, malignant migrating partial seizures of infancy, autosomaldominant nocturnal frontal lobe epilepsy, sudden expected death inepilepsy (SUDEP), KCNQ2 epileptic encephalopathy, or KCNT1 epilepticencephalopathy) comprising administering to a subject in need thereof acompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; A is aryl or heteroaryl (e.g., 6-memberedaryl or heteroaryl), wherein aryl and heteroaryl are optionallysubstituted by one or more R³; R′ is hydrogen or alkyl; R isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c); each R^(c) is independently hydrogen, alkyl,aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.

A compound of the present invention (e.g., a compound of Formula (I),(I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j),(I-k), or (I-l)) may also be used to treat an epileptic encephalopathy,wherein the subject has a mutation in one or more of ALDH7A1, ALG13,ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8, CNTNAP2,CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3, GABRG2,GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2, KCNB1, KCNC1,KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1, PCDH19, PLCB1,PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2, SCN1A, SCN1B,SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22, SLC2A1, SLC35A2,SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B, STXBP1, SYN1,SYNGAP1, SZT2, TBC1D24, and WWOX.

In some embodiments, the methods described herein further compriseidentifying a subject having a mutation in one or more of ALDH7A1,ALG13, ARHGEF9, ARX, ASAH1, CDKL5, CHD2, CHRNA2, CHRNA4, CHRNB2, CLN8,CNTNAP2, CPA6, CSTB, DEPDC5, DNM1, EEF1A2, EPM2A, EPM2B, GABRA1, GABRB3,GABRG2, GNAO1, GOSR2, GRIN1, GRIN2A, GRIN2B, HCN1, IER3IP1, KCNA2,KCNB1, KCNC1, KCNMA1, KCNQ2, KCNQ3, KCNT1, KCTD7, LGI1, MEF2C, NHLRC1,PCDH19, PLCB1, PNKP, PNPO, PRICKLE1, PRICKLE2, PRRT2, RELN, SCARB2,SCN1A, SCN1B, SCN2A, SCN8A, SCN9A, SIAT9, SIK1, SLC13A5, SLC25A22,SLC2A1, SLC35A2, SLC6A1, SNIP1, SPTAN1, SRPX2, ST3GAL3, STRADA, STX1B,STXBP1, SYN1, SYNGAP1, SZT2, TBC1D24, and WWOX prior to administrationof a compound described herein (e.g., a compound of Formula (I), (I-a),(I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h), (I-i), (I-j), (I-k), or(I-l)).

Neurodevelopmental Disorders

The compounds described herein may be useful in the treatment of aneurodevelopmental disorder. In some embodiments, the neurodevelopmentaldisorder comprises autism, autism with epilepsy, tuberous sclerosis,Fragile X syndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome,22q13.3 Deletion syndrome, Prader-Willi syndrome, velocardiofacialsyndrome, Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorderwith epilepsy. In some embodiments, the methods described herein furthercomprise identifying a subject having a neurodevelopmental disorder(e.g., autism, autism with epilepsy, tuberous sclerosis, Fragile Xsyndrome, Rett syndrome, Angelman syndrome, Dup15q syndrome, 22q13.3Deletion syndrome, Prader-Willi syndrome, velocardiofacial syndrome,Smith-Lemli-Opitz syndrome, or a neurodevelopmental disorder withepilepsy) prior to administration of a compound described herein (e.g.,a compound of Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f),(I-g), (I-h), (I-i), (I-j), (I-k), or (I-l)).

In one aspect, the present invention features a method of treating aneurodevelopmental disorder (e.g., autism, autism with epilepsy,tuberous sclerosis, Fragile X syndrome, Rett syndrome, Angelmansyndrome, Dup15q syndrome, 22q13.3 Deletion syndrome, Prader-Willisyndrome, velocardiofacial syndrome, Smith-Lemli-Opitz syndrome, or aneurodevelopmental disorder with epilepsy) comprising administering to asubject in need thereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; A is aryl or heteroaryl (e.g., 6-memberedaryl or heteroaryl), wherein aryl and heteroaryl are optionallysubstituted by one or more R³; R′ is hydrogen or alkyl; R¹ isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c) each R^(c) is independently hydrogen, alkyl,aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.Pain

The compounds described herein may be useful in the treatment of pain.In some embodiments, the pain comprises neuropathic pain, trigeminalneuralgia, migraine, hemiplegic migraine, familial hemiplegic migraine,familial hemiplegic migraine type 3, cluster headache, trigeminalneuralgia, cerebellar ataxia, or a related headache disorder. In someembodiments, the methods described herein further comprise identifying asubject having pain (e.g., neuropathic pain, trigeminal neuralgia,migraine, hemiplegic migraine, familial hemiplegic migraine, familialhemiplegic migraine type 3, cluster headache, trigeminal neuralgia,cerebellar ataxia, or a related headache disorder) prior toadministration of a compound described herein (e.g., a compound ofFormula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h),(I-i), (I-j), (I-k), or (I-l)).

In one aspect, the present invention features a method of treating pain(e.g., neuropathic pain, trigeminal neuralgia, migraine, hemiplegicmigraine, familial hemiplegic migraine, familial hemiplegic migrainetype 3, cluster headache, trigeminal neuralgia, cerebellar ataxia, or arelated headache disorder) comprising administering to a subject in needthereof a compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; A is aryl or heteroaryl (e.g., 6-memberedaryl or heteroaryl), wherein aryl and heteroaryl are optionallysubstituted by one or more R³; R′ is hydrogen or alkyl; R isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c); each R^(c) is independently hydrogen, alkyl,aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.Neuromuscular Disorders

The compounds described herein may be useful in the treatment of aneuromuscular disorder. In some embodiments, the neuromuscular disordercomprises amyotrophic lateral sclerosis, multiple sclerosism, myotonia,paramyotonia congenita, potassium-aggravated myotonia, periodicparalysis, hyperkalemic periodic paralysis, hypokalemic periodicparalysis, or laryngospasm with SCN4A mutation. In some embodiments, themethods described herein further comprise identifying a subject having aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)prior to administration of a compound described herein (e.g., a compoundof Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f), (I-g), (I-h),(I-i), (I-j), (I-k), or (I-l)).

In one aspect, the present invention features a method of treating aneuromuscular disorder (e.g., amyotrophic lateral sclerosis, multiplesclerosism, myotonia, paramyotonia congenita, potassium-aggravatedmyotonia, periodic paralysis, hyperkalemic periodic paralysis,hypokalemic periodic paralysis, or laryngospasm with SCN4A mutation)comprising administering to a subject in need thereof a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein each of X, Y, andZ is independently N or CR′; A is aryl or heteroaryl (e.g., 6-memberedaryl or heteroaryl), wherein aryl and heteroaryl are optionallysubstituted by one or more R³; R′ is hydrogen or alkyl; R isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR^(c); each R^(c) is independently hydrogen, alkyl,aryl, carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.Other Disorders

In some embodiments, a compound of the present invention (e.g., acompound of Formula (I), (I-a), (I-b), (I-c), (I-d), (I-e), (I-f),(I-g), (I-h), (I-i), (I-j), (I-k), or (I-l)) may have appropriatepharmacokinetic properties such that they may active with regard to thecentral and/or peripheral nervous system. In some embodiments, thecompounds provided herein are used to treat a cardiovascular diseasesuch as atrial and ventricular arrhythmias, including atrialfibrillation, Prinzmetal's (variant) angina, stable angina, unstableangina, ischemia and reperfusion injury in cardiac, kidney, liver andthe brain, exercise induced angina, pulmonary hypertension, congestiveheart disease including diastolic and systolic heart failure, recurrentischemia, cerebral ischemia, stroke, renal ischemia, ischemia associatedwith organ transplant, acute coronary syndrome, peripheral arterialdisease, intermittent claudication, and myocardial infarction. In someembodiments, the compounds provided herein may be used in the treatmentof diseases affecting the neuromuscular system resulting in itching,seizures, or paralysis, or in the treatment of diabetes or reducedinsulin sensitivity, and disease states related to diabetes, such asdiabetic peripheral neuropathy. In some embodiments, a disclosed methodcomprises administering the pharmaceutical composition.

In one aspect, the present disclosure provides a method of treating aneurological disorder or a psychiatric disorder, wherein the methodcomprises administering to a subject in need thereof a compound ofFormula (I):

or a pharmaceutically acceptable salt thereof, wherein: each of X, Y,and Z is independently N or CR′; A is aryl or heteroaryl (e.g.,6-membered aryl or heteroaryl), wherein aryl and heteroaryl areoptionally substituted by one or more R³; R′ is hydrogen or alkyl; R isindependently hydrogen, alkyl, carbocyclyl, heterocyclyl, halo, orcyano, wherein alkyl, carbocyclyl, and heterocyclyl are optionallysubstituted with one or more R⁴; R² is hydrogen, alkyl, halo, or cyano,wherein each alkyl is optionally substituted with one or more R⁴; eachR³ is independently alkyl, carbocyclyl, heterocyclyl, halo, cyano,nitro, or —OR^(c), wherein alkyl, carbocyclyl, and heterocyclyl areoptionally substituted with one or more R⁵; each of R⁴ and R⁵ isindependently alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, halo,cyano, nitro, or —OR; each R^(c) is independently hydrogen, alkyl, aryl,carbocyclyl, heterocyclyl, or heteroaryl, wherein alkyl, aryl, orheteroaryl is optionally substituted by one or more R⁶; each R^(d) isindependently hydrogen or alkyl; and each R⁶ is independently alkyl,carbocyclyl, heterocyclyl, halo, cyano, nitro, or —OH, wherein alkyl isoptionally substituted with one or more halo.

In some embodiments, X is CR² (e.g., —CH).

In some embodiments, X is N.

In some embodiments, A is aryl (e.g., phenyl).

In some embodiments, A is phenyl substituted by 1 R³ (e.g., wherein R³is in the para position).

In some embodiments, R³ is —OR^(c).

In some embodiments, R^(c) is alkyl substituted by one or more R⁶.

In some embodiments, R⁶ is halo (e.g., fluoro).

In some embodiments, R³ is —OCF₃.

In some embodiments, R¹ is hydrogen.

In some embodiments, R¹ is alkyl (e.g., substituted with 1-4 R⁴).

In some embodiments, R⁴ is halo (e.g., fluoro).

In some embodiments, R¹ is —CF₃.

In any and all aspects, in some embodiments, the compound of Formula (I)is selected from:

or a pharmaceutically acceptable salt thereof. Also provided herein is amethod of treating a neurological disorder or a psychiatric disorder,wherein the method comprises administering to a subject in need thereofa compound disclosed herein, or a pharmaceutically acceptable saltthereof or a pharmaceutical composition disclosed herein.Pharmaceutical Compositions and Routes of Administration

Compounds provided in accordance with the present invention are usuallyadministered in the form of pharmaceutical compositions. This inventiontherefore provides pharmaceutical compositions that contain, as theactive ingredient, one or more of the compounds described, or apharmaceutically acceptable salt or ester thereof, and one or morepharmaceutically acceptable excipients, carriers, including inert soliddiluents and fillers, diluents, including sterile aqueous solution andvarious organic solvents, permeation enhancers, solubilizers andadjuvants. The pharmaceutical compositions may be administered alone orin combination with other therapeutic agents. Such compositions areprepared in a manner well known in the pharmaceutical art (see, e.g.,Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia,Pa. 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rdEd. (G. S. Banker & C. T. Rhodes, Eds.)

The pharmaceutical compositions may be administered in either single ormultiple doses by any of the accepted modes of administration of agentshaving similar utilities, for example as described in those patents andpatent applications incorporated by reference, including rectal, buccal,intranasal and transdermal routes, by intra-arterial injection,intravenously, intraperitoneally, parenterally, intramuscularly,subcutaneously, orally, topically, as an inhalant, or via an impregnatedor coated device such as a stent, for example, or an artery-insertedcylindrical polymer.

One mode for administration is parenteral, particularly by injection.The forms in which the novel compositions of the present invention maybe incorporated for administration by injection include aqueous or oilsuspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, orpeanut oil, as well as elixirs, mannitol, dextrose, or a sterile aqueoussolution, and similar pharmaceutical vehicles. Aqueous solutions insaline are also conventionally used for injection, but less preferred inthe context of the present invention. Ethanol, glycerol, propyleneglycol, liquid polyethylene glycol, and the like (and suitable mixturesthereof), cyclodextrin derivatives, and vegetable oils may also beemployed. The proper fluidity can be maintained, for example, by the useof a coating, such as lecithin, by the maintenance of the requiredparticle size in the case of dispersion and by the use of surfactants.The prevention of the action of microorganisms can be brought about byvarious antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating a compoundaccording to the present invention in the required amount in theappropriate solvent with various other ingredients as enumerated above,as required, followed by filtered sterilization. Generally, dispersionsare prepared by incorporating the various sterilized active ingredientsinto a sterile vehicle which contains the basic dispersion medium andthe required other ingredients from those enumerated above. In the caseof sterile powders for the preparation of sterile injectable solutions,the preferred methods of preparation are vacuum-drying and freeze-dryingtechniques which yield a powder of the active ingredient plus anyadditional desired ingredient from a previously sterile-filteredsolution thereof.

Oral administration is another route for administration of compounds inaccordance with the invention. Administration may be via capsule orenteric coated tablets, or the like. In making the pharmaceuticalcompositions that include at least one compound described herein, theactive ingredient is usually diluted by an excipient and/or enclosedwithin such a carrier that can be in the form of a capsule, sachet,paper or other container. When the excipient serves as a diluent, it canbe in the form of a solid, semi-solid, or liquid material (as above),which acts as a vehicle, carrier or medium for the active ingredient.Thus, the compositions can be in the form of tablets, pills, powders,lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions,syrups, aerosols (as a solid or in a liquid medium), ointmentscontaining, for example, up to 10% by weight of the active compound,soft and hard gelatin capsules, sterile injectable solutions, andsterile packaged powders.

Some examples of suitable excipients include lactose, dextrose, sucrose,sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates,tragacanth, gelatin, calcium silicate, microcrystalline cellulose,polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulations can additionally include: lubricating agentssuch as talc, magnesium stearate, and mineral oil; wetting agents;emulsifying and suspending agents; preserving agents such as methyl andpropylhydroxy-benzoates; sweetening agents; and flavoring agents.

The compositions of the invention can be formulated so as to providequick, sustained or delayed release of the active ingredient afteradministration to the patient by employing procedures known in the art.Controlled release drug delivery systems for oral administration includeosmotic pump systems and dissolutional systems containing polymer-coatedreservoirs or drug-polymer matrix formulations. Examples of controlledrelease systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525;4,902,514; and 5,616,345. Another formulation for use in the methods ofthe present invention employs transdermal delivery devices (“patches”).Such transdermal patches may be used to provide continuous ordiscontinuous infusion of the compounds of the present invention incontrolled amounts. The construction and use of transdermal patches forthe delivery of pharmaceutical agents is well known in the art. See,e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patchesmay be constructed for continuous, pulsatile, or on demand delivery ofpharmaceutical agents.

The compositions are preferably formulated in a unit dosage form. Theterm “unit dosage forms” refers to physically discrete units suitable asunitary dosages for human subjects and other mammals, each unitcontaining a predetermined quantity of active material calculated toproduce the desired therapeutic effect, in association with a suitablepharmaceutical excipient (e.g., a tablet, capsule, ampoule). Thecompounds are generally administered in a pharmaceutically effectiveamount. Preferably, for oral administration, each dosage unit containsfrom 1 mg to 2 g of a compound described herein, and for parenteraladministration, preferably from 0.1 to 700 mg of a compound a compounddescribed herein. It will be understood, however, that the amount of thecompound actually administered usually will be determined by aphysician, in the light of the relevant circumstances, including thecondition to be treated, the chosen route of administration, the actualcompound administered and its relative activity, the age, weight, andresponse of the individual patient, the severity of the patient'ssymptoms, and the like.

For preparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical excipient to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules.

The tablets or pills of the present invention may be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction, or to protect from the acid conditions of the stomach. Forexample, the tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer thatserves to resist disintegration in the stomach and permit the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol, andcellulose acetate.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable, aqueous or organic solvents,or mixtures thereof, and powders. The liquid or solid compositions maycontain suitable pharmaceutically acceptable excipients as describedsupra. Preferably, the compositions are administered by the oral ornasal respiratory route for local or systemic effect. Compositions inpreferably pharmaceutically acceptable solvents may be nebulized by useof inert gases. Nebulized solutions may be inhaled directly from thenebulizing device or the nebulizing device may be attached to a facemasktent, or intermittent positive pressure breathing machine. Solution,suspension, or powder compositions may be administered, preferablyorally or nasally, from devices that deliver the formulation in anappropriate manner.

In some embodiments, a pharmaceutical composition comprises a disclosedcompound, or pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.

Combination Therapy

A compound or composition described herein (e.g., for use in modulatinga sodium ion channel, e.g., the late sodium (INaL) current) may beadministered in combination with another agent or therapy. A subject tobe administered a compound disclosed herein may have a disease,disorder, or condition, or a symptom thereof, that would benefit fromtreatment with another agent or therapy. These diseases or conditionscan relate to epilepsy or an epilepsy syndrome, a neurodevelopmentaldisorder, pain, or a neuromuscular disorder.

Antiepilepsy Agents

Anti-epilepsy agents include brivaracetam, carbamazepine, clobazam,clonazepam, diazepam, divalproex, eslicarbazepine, ethosuximide,ezogabine, felbamate, gabapentin, lacosamide, lamotrigine,levetiracetam, lorazepam, oxcarbezepine, permpanel, phenobarbital,phenytoin, pregabalin, primidone, rufinamide, tigabine, topiramate,valproic acid, vigabatrin, zonisamide, and cannabidiol.

Cardiovascular Agent Combination Therapy

Cardiovascular related diseases or conditions that can benefit from acombination treatment of the sodium channel blockers of the inventionwith other therapeutic agents include, without limitation, anginaincluding stable angina, unstable angina (UA), exercised-induced angina,variant angina, arrhythmias, intermittent claudication, myocardialinfarction including non-STE myocardial infarction (NSTEMI), pulmonaryhypertension including pulmonary arterial hypertension, heart failureincluding congestive (or chronic) heart failure and diastolic heartfailure and heart failure with preserved ejection fraction (diastolicdysfunction), acute heart failure, or recurrent ischemia.

Therapeutic agents suitable for treating cardiovascular related diseasesor conditions include anti-anginals, heart failure agents,antithrombotic agents, antiarrhythmic agents, antihypertensive agents,and lipid lowering agents.

The co-administration of the sodium channel blockers of the inventionwith therapeutic agents suitable for treating cardiovascular relatedconditions allows enhancement in the standard of care therapy thepatient is currently receiving.

Anti-Anginals

Anti-anginals include beta-blockers, calcium channel blockers, andnitrates. Beta blockers reduce the heart's need for oxygen by reducingits workload resulting in a decreased heart rate and less vigorous heartcontraction. Examples of beta-blockers include acebutolol (Sectral),atenolol (Tenormin), betaxolol (Kerlone), bisoprolol/hydrochlorothiazide(Ziac), bisoprolol (Zebeta), carteolol (Cartrol), esmolol (Brevibloc),labetalol (Normodyne, Trandate), metoprolol (Lopressor, Toprol XL),nadolol (Corgard), propranolol (Inderal), sotalol (Betapace), andtimolol (Blocadren).

Nitrates dilate the arteries and veins thereby increasing coronary bloodflow and decreasing blood pressure. Examples of nitrates includenitroglycerin, nitrate patches, isosorbide dinitrate, andisosorbide-5-mononitrate.

Calcium channel blockers prevent the normal flow of calcium into thecells of the heart and blood vessels causing the blood vessels to relaxthereby increasing the supply of blood and oxygen to the heart. Examplesof calcium channel blockers include amlodipine (Norvasc, Lotrel),bepridil (Vascor), diltiazem (Cardizem, Tiazac), felodipine (Plendil),nifedipine (Adalat, Procardia), nimodipine (Nimotop), nisoldipine(Sular), verapamil (Calan, Isoptin, Verelan), and nicardipine.

Heart Failure Agents

Agents used to treat heart failure include diuretics, ACE inhibitors,vasodilators, and cardiac glycosides. Diuretics eliminate excess fluidsin the tissues and circulation thereby relieving many of the symptoms ofheart failure. Examples of diuretics include hydrochlorothiazide,metolazone (Zaroxolyn), furosemide (Lasix), bumetanide (Bumex),spironolactone (Aldactone), and eplerenone (nspra).

Angiotensin converting enzyme (ACE) inhibitors reduce the workload onthe heart by expanding the blood vessels and decreasing resistance toblood flow. Examples of ACE inhibitors include benazepril (Lotensin),captopril (Capoten), enalapril (Vasotec), fosinopril (Monopril),lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril(Aceon), quinapril (Accupril), ramipril (Altace), and trandolapril(Mavik).

Vasodilators reduce pressure on the blood vessels by making them relaxand expand. Examples of vasodilators include hydralazine, diazoxide,prazosin, clonidine, and methyldopa. ACE inhibitors, nitrates, potassiumchannel activators, and calcium channel blockers also act asvasodilators.

Cardiac glycosides are compounds that increase the force of the heart'scontractions. These compounds strengthen the pumping capacity of theheart and improve irregular heartbeat activity. Examples of cardiacglycosides include digitalis, digoxin, and digitoxin.

Antithrombotic Agents

Antithrombotics inhibit the clotting ability of the blood. There arethree main types of antithrombotics—platelet inhibitors, anticoagulants,and thrombolytic agents.

Platelet inhibitors inhibit the clotting activity of platelets, therebyreducing clotting in the arteries. Examples of platelet inhibitorsinclude acetylsalicylic acid (aspirin), ticlopidine, clopidogrel(plavix), dipyridamole, cilostazol, persantine sulfinpyrazone,dipyridamole, indomethacin, and glycoprotein IIb/IIIa inhibitors, suchas abciximab, tirofiban, and eptifibatide (Integrelin). Beta blockersand calcium channel blockers also have a platelet-inhibiting effect.

Anticoagulants prevent blood clots from growing larger and prevent theformation of new clots. Examples of anticoagulants include bivalirudin(Angiomax), warfarin (Coumadin), unfractionated heparin, low molecularweight heparin, danaparoid, lepirudin, and argatroban.

Thrombolytic agents act to break down an existing blood clot. Examplesof thrombolytic agents include streptokinase, urokinase, andtenecteplase (TNK), and tissue plasminogen activator (t-PA).

Antiarrhythmic Agents

Antiarrhythmic agents are used to treat disorders of the heart rate andrhythm. Examples of antiarrhythmic agents include amiodarone,dronedarone, quinidine, procainamide, lidocaine, and propafenone.Cardiac glycosides and beta blockers are also used as antiarrhythmicagents.

Combinations with amiodarone and dronedarone are of particular interestgiven the recently discovered synergistic effects of the sodium channelblocker ranolazine and amioarone and dronedarone.

Antihypertensive Agents

Antihypertensive agents are used to treat hypertension, a condition inwhich the blood pressure is consistently higher than normal.Hypertension is associated with many aspects of cardiovascular disease,including congestive heart failure, atherosclerosis, and clot forillation. Examples of antihypertensive agents include alpha-1-adrenergicantagonists, such as prazosin (Minipress), doxazosin mesylate (Cardura),prazosin hydrochloride (Minipress), prazosin, polythiazide (Minizide),and terazosin hydrochloride (Hytrin); beta-adrenergic antagonists, suchas propranolol (Inderal), nadolol (Corgard), timolol (Blocadren),metoprolol (Lopressor), and pindolol (Visken); centralalpha-adrenoceptor agonists, such as clonidine hydrochloride (Catapres),clonidine hydrochloride and chlorthalidone (Clorpres, Combipres),guanabenz Acetate (Wytensin), guanfacine hydrochloride (Tenex),methyldopa (Aldomet), methyldopa and chlorothiazide (Aldoclor),methyldopa and hydrochlorothiazide (Aldoril); combinedalpha/beta-adrenergic antagonists, such as labetalol (Normodyne,Trandate), Carvedilol (Coreg); adrenergic neuron blocking agents, suchas guanethidine (ismelin), reserpine (Serpasil); central nervoussystem-acting antihypertensives, such as clonidine (Catapres),methyldopa (Aldomet), guanabenz (Wytensin); anti-angiotensin II agents;ACE inhibitors, such as perindopril (Aceon) captopril (Capoten),enalapril (Vasotec), lisinopril (Prinivil, Zestril); angiotensin-IIreceptor antagonists, such as Candesartan (Atacand), Eprosartan(Teveten), Irbesartan (Avapro), Losartan (Cozaar), Telmisartan(Micardis), Valsartan (Diovan); calcium channel blockers, such asverapamil (Calan, Isoptin), diltiazem (Cardizem), nifedipine (Adalat,Procardia); diuretics; direct vasodilators, such as nitroprusside(Nipride), diazoxide (Hyperstat IV), hydralazine (Apresoline), minoxidil(Loniten), verapamil; and potassium channel activators, such asaprikalim, bimakalim, cromakalim, emakalim, nicorandil, and pinacidil.

Lipid Lowering Agents

Lipid lowering agents are used to lower the amounts of cholesterol orfatty sugars present in the blood. Examples of lipid lowering agentsinclude bezafibrate (Bezalip), ciprofibrate (Modalim), and statins, suchas atorvastatin (Lipitor), fluvastatin (Lescol), lovastatin (Mevacor,Altocor), mevastatin, pitavastatin (Livalo, Pitava) pravastatin(Lipostat), rosuvastatin (Crestor), and simvastatin (Zocor).

In this invention, the patient presenting with an acute coronary diseaseevent often suffers from secondary medical conditions such as one ormore of a metabolic disorder, a pulmonary disorder, a peripheralvascular disorder, or a gastrointestinal disorder. Such patients canbenefit from treatment of a combination therapy comprising administeringto the patient ranolazine in combination with at least one therapeuticagent.

Pulmonary Disorders Combination Therapy

Pulmonary disorder refers to any disease or condition related to thelungs. Examples of pulmonary disorders include, without limitation,asthma, chronic obstructive pulmonary disease (COPD), bronchitis, andemphysema.

Examples of therapeutics agents used to treat pulmonary disordersinclude bronchodilators including beta2 agonists and anticholinergics,corticosteroids, and electrolyte supplements. Specific examples oftherapeutic agents used to treat pulmonary disorders includeepinephrine, terbutaline (Brethaire, Bricanyl), albuterol (Proventil),salmeterol (Serevent, Serevent Diskus), theophylline, ipratropiumbromide (Atrovent), tiotropium (Spiriva), methylprednisolone(Solu-Medrol, Medrol), magnesium, and potassium.

Metabolic Disorders Combination Therapy

Examples of metabolic disorders include, without limitation, diabetes,including type I and type II diabetes, metabolic syndrome, dyslipidemia,obesity, glucose intolerance, hypertension, elevated serum cholesterol,and elevated triglycerides.

Examples of therapeutic agents used to treat metabolic disorders includeantihypertensive agents and lipid lowering agents, as described in thesection “Cardiovascular Agent Combination Therapy” above. Additionaltherapeutic agents used to treat metabolic disorders include insulin,sulfonylureas, biguanides, alpha-glucosidase inhibitors, and incretinmimetics.

Peripheral Vascular Disorders Combination Therapy

Peripheral vascular disorders are disorders related to the blood vessels(arteries and veins) located outside the heart and brain, including, forexample peripheral arterial disease (PAD), a condition that developswhen the arteries that supply blood to the internal organs, arms, andlegs become completely or partially blocked as a result ofatherosclerosis.

Gastrointestinal Disorders Combination Therapy

Gastrointestinal disorders refer to diseases and conditions associatedwith the gastrointestinal tract. Examples of gastrointestinal disordersinclude gastroesophageal reflux disease (GERD), inflammatory boweldisease (IBD), gastroenteritis, gastritis and peptic ulcer disease, andpancreatitis.

Examples of therapeutic agents used to treat gastrointestinal disordersinclude proton pump inhibitors, such as pantoprazole (Protonix),lansoprazole (Prevacid), esomeprazole (Nexium), omeprazole (Prilosec),rabeprazole; H2 blockers, such as cimetidine (Tagamet), ranitidine(Zantac), famotidine (Pepcid), nizatidine (Axid); prostaglandins, suchas misoprostoL (Cytotec); sucralfate; and antacids.

Antibiotics, Analgesics, Antidepressants and Anti-Anxiety AgentsCombination Therapy

Patients presenting with an acute coronary disease event may exhibitconditions that benefit from administration of therapeutic agent oragents that are antibiotics, analgesics, antidepressant and anti-anxietyagents in combination with ranolazine.

Antibiotics

Antibiotics are therapeutic agents that kill, or stop the growth of,microorganisms, including both bacteria and fungi. Example of antibioticagents include .beta.-Lactam antibiotics, including penicillins(amoxicillin), cephalosporins, such as cefazolin, cefuroxime, cefadroxil(Duricef), cephalexin (Keflex), cephradine (Velosef), cefaclor (Ceclor),cefuroxime axtel (Ceftin), cefprozil (Cefzil), loracarbef (Lorabid),cefixime (Suprax), cefpodoxime proxetil (Vantin), ceftibuten (Cedax),cefdinir (Omnicef), ceftriaxone (Rocephin), carbapenems, andmonobactams; tetracyclines, such as tetracycline; macrolide antibiotics,such as erythromycin; aminoglycosides, such as gentamicin, tobramycin,amikacin; quinolones such as ciprofloxacin; cyclic peptides, such asvancomycin, streptogramins, polymyxins; lincosamides, such asclindamycin; oxazolidinoes, such as linezolid; and sulfa antibiotics,such as sulfisoxazole.

Analgesics

Analgesics are therapeutic agents that are used to relieve pain.Examples of analgesics include opiates and morphinomimetics, such asfentanyl and morphine; paracetamol; NSAIDs, and COX-2 inhibitors. Giventhe ability of the sodium channel blockers of the invention to treatneuropathic pain via inhibition of the Nav 1.7 and 1.8 sodium channels,combination with analgesics are particularly envisioned. See U.S. PatentApplication Publication 20090203707.

Antidepressant and Anti-Anxiety Agents

Antidepressant and anti-anxiety agents include those agents used totreat anxiety disorders, depression, and those used as sedatives andtranquillizers. Examples of antidepressant and anti-anxiety agentsinclude benzodiazepines, such as diazepam, lorazepam, and midazolam;benzodiazepines; barbiturates; glutethimide; chloral hydrate;meprobamate; sertraline (Zoloft, Lustral, Apo-Sertral, Asentra, Gladem,Serlift, Stimuloton); escitalopram (Lexapro, Cipralex); fluoxetine(Prozac, Sarafem, Fluctin, Fontex, Prodep, Fludep, Lovan); venlafaxine(Effexor XR, Efexor); citalopram (Celexa, Cipramil, Talohexane);paroxetine (Paxil, Seroxat, Aropax); trazodone (Desyrel); amitriptyline(Elavil); and bupropion (Wellbutrin, Zyban). Antidepressant andanti-anxiety agents may include neuroactive steroid and ketamine andrelated NMDA receptor antagonists.

Accordingly, one aspect of the invention provides for a compositioncomprising the sodium channel blockers of the invention and at least onetherapeutic agent. In an alternative embodiment, the compositioncomprises the sodium channel blockers of the invention and at least twotherapeutic agents. In further alternative embodiments, the compositioncomprises the sodium channel blockers of the invention and at leastthree therapeutic agents, the sodium channel blockers of the inventionand at least four therapeutic agents, or the sodium channel blockers ofthe invention and at least five therapeutic agents.

The methods of combination therapy include co-administration of a singleformulation containing the sodium channel blockers of the invention andtherapeutic agent or agents, essentially contemporaneous administrationof more than one formulation comprising the sodium channel blocker ofthe invention and therapeutic agent or agents, and consecutiveadministration of a sodium channel blocker of the invention andtherapeutic agent or agents, in any order, wherein preferably there is atime period where the sodium channel blocker of the invention andtherapeutic agent or agents simultaneously exert their therapeuticeffect.

EXAMPLES

In order that the invention described herein may be more fullyunderstood, the following examples are set forth. The synthetic andbiological examples described in this application are offered toillustrate the compounds, pharmaceutical compositions and methodsprovided herein and are not to be construed in any way as limiting theirscope.

The compounds provided herein can be prepared from readily availablestarting materials using the following general methods and procedures.It will be appreciated that where typical or preferred processconditions (i.e., reaction temperatures, times, mole ratios ofreactants, solvents, pressures, etc.) are given, other processconditions can also be used unless otherwise stated. Optimal reactionconditions may vary with the particular reactants or solvent used, butsuch conditions can be determined by one skilled in the art by routineoptimization.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. The choice of asuitable protecting group for a particular functional group as well assuitable conditions for protection and deprotection are well known inthe art. For example, numerous protecting groups, and their introductionand removal, are described in T. W. Greene and P. G. M. Wuts, ProtectingGroups in Organic Synthesis, Second Edition, Wiley, New York, 1991, andreferences cited therein.

The compounds provided herein may be isolated and purified by knownstandard procedures. Such procedures include recrystallization,filtration, flash chromatography, trituration, high pressure liquidchromatography (HPLC), or supercritical fluid chromatography (SFC). Notethat flash chromatography may either be performed manually or via anautomated system. The compounds provided herein may be characterized byknown standard procedures, such as nuclear magnetic resonancespectroscopy (NMR) or liquid chromatography mass spectrometry (LCMS).NMR chemical shifts are reported in part per million (ppm) and aregenerated using methods well known to those of skill in the art.

Exemplary general methods for analytical LCMS include Method A (XtimateC₁₈ (2.1 mm×30 mm, 3 μm); A=H₂O (0.04% TFA) and B═CH₃CN (0.02% TFA); 50°C.; 1.2 mL/min; 10-80% B over 0.9 minutes, then 80% B for 0.6 minutes)and Method B (Chromolith Flash RP-18 endcapped C₁₈ (2 mm×25 mm); A=H₂O(0.04% TFA) and B═CH₃CN (0.02% TFA); 50° C.; 1.5 mL/min; 5-95% B over0.7 minutes, then 95% B for 0.4 minutes).

List of Abbreviations

NIS N-iodosuccinimide

AcOH acetic acid

EtOAc ethyl acetate

DMF N,N-dimethylformamide

THF tetrahydrofuran

MeOH methanol

DCM dichloromethane

EtOH ethanol

TFA trifluoroacetic acid

dppf 1,1′-bis(diphenylphosphino)ferrocene

Et₃SiH triethylsilane

DBU 1,8-diazabicyclo(5.4.0)undec-7-ene

DMSO dimethyl sulfoxide

TMSCF₃ trifluoromethyltrimethylsilane

Pd(t-Bu₃P)₂ bis(tri-tert-butylphosphine)palladium(O)

DAST diethylaminosulfur trifluoride

DIBAL-H diisobutylaluminium hydride

Pd(dba)₃ tris(dibenzylideneacetone)dipalladium(O)

Example 1: Synthesis of Compound 1

Synthesis of A-2

A mixture of A-1 (1.00 g, 7.22 mmol, 1.00 eq),[4-(trifluoromethoxy)phenyl]boronic acid (1.93 g, 9.39 mmol, 1.30 eq),Pd(t-Bu₃P)₂ (184.49 mg, 361.00 umol, 0.05 eq) and K₃PO₄ (3.07 g, 14.44mmol, 2.00 eq) in dioxane (50.00 mL) and H₂O (10.00 mL) was stirred at80° C. for 12 hours under N₂. The mixture was concentrated, and theresidue was diluted with H₂O (50 mL) and extracted with EtOAc (100mL×2). The combined organic phase was washed with water (50 mL×2) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give aresidue that was purified by silica gel (EtOAc in PE=0% to 10% to 15%)to afford A-2 (1.50 g, 5.68 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ=8.79 (d, 1H), 7.90 (d, 1H), 7.74-7.64 (m, 3H), 7.40 (d, 2H).

Synthesis of A-3

A mixture of A-2 (500.00 mg, 1.89 mmol, 1.00 eq) and 10% Pd/C (300.00mg) in AcOH (2.00 mL) and EtOAc (2.00 mL) was stirred under H₂ (15 psi)at 20° C. for 16 hours. The mixture was filtered through Celite, elutedwith EtOAc (30 mL×2), concentrated, and the residue was diluted withEtOAc (150 mL). The combined organic phase was washed with saturatedNa₂CO₃ (30 mL), water (20 mL) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to afford A-3 (550.00 mg, crude) as an oil. ¹HNMR (400 MHZ, CDCl₃) δ=8.63 (d, 1H), 7.67 (d, 2H), 7.51 (s, 1H),7.40-7.30 (m, 3H), 4.13 (s, 2H)

Synthesis of A-4

A mixture of A-3 (550.00 mg, 2.05 mmol, 1.00 eq) in HCOOH (10.00 mL) wasstirred at 100° C. for 5 hours. The mixture was then concentrated to theresidue that was diluted with H₂O (30 mL) and extracted with EtOAc (50mL×2). The combined organic phase was washed with water (20 mL×2) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to affordA-4 (690.00 mg, 1.19 mmol, HCOOH salt) as an oil. LCMS R_(t)=0.711 minin 1.5 min chromatography, MS ESI calcd. for C₁₄H₁₂F₃N₂O₂ [M+H]⁺ 297.1,found 296.9.

Synthesis of Compound 1

A mixture of A-4 (650.00 mg, 1.90 mmol, 1.00 eq, HCOOH salt) in POCl₃(8.00 mL) was stirred at 100° C. for 1 hour. The mixture wasconcentrated to a residue that was poured into ice-water (30 mL),basified with Na₂CO₃ (solid) to pH˜9, and extracted with EtOAc (50mL×2). The combined organic phase was washed with water (20 mL×2) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by silica gel (EtOAc inPE=30% to 50% to 80%) and Prep-TLC (DCM/EtOAc=1/1) to afford Compound 1(4.67 mg, 16.78 μmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ=8.15 (s,1H), 8.01 (d, 1H), 7.68-7.58 (m, 3H), 7.52 (s, 1H), 7.32 (d, 2H), 6.84(dd, 1H). LCMS R_(t)=0.925 min in 2.0 min chromatography, MS ESI calcd.for C₁₄H₁₀F₃N₂O [M+H]⁺ 279.1, found 278.9.

Example 2: Synthesis of Compound 2

Synthesis of A-5

To a mixture of NaHCO₃ (169.09 mg, 2.01 mmol, 4.00 eq) and Compound 1(140.00 mg, 503.18 umol, 1.00 eq) in H₂O (2.00 mL) and EtOH (4.00 mL)was added 2 (178.80 mg, 704.45 μmol, 1.40 eq). The mixture was stirredat 20° C. for 8 hours. The mixture was quenched by sat. Na₂S₂O₃ (3 mL)and extracted with EtOAc (30 mL×2). The combined organic phase waswashed with brine (10 mL), dried over Na₂SO₄, filtered and concentratedto give a residue that was purified by Prep-TLC (PET/EtOAc=1/1) toafford A-5 (160.00 mg, 379.64 μmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ=8.16 (s, 1H), 8.00 (dd, 1H), 7.66 (d, 2H), 7.48 (s, 1H), 7.33 (d, 2H),6.89 (dd, 1H). LCMS R_(t)=0.891 min in 1.5 min chromatography, MS ESIcalcd. for C₁₄H₉F₃IN₂O [M+H]⁺ 405.0, found 404.8.

Synthesis of Compound 2

To a mixture of AgF (65.30 mg, 514.70 μmol, 2.60 eq) in DMF (5.00 mL)was added TMSCF₃ (90.08 mg, 633.47 umol, 3.20 eq), then the mixture wasstirred at 20° C. for 1 hour. Cu (50.32 mg, 791.84 umol, 4.00 eq) wasthen added, then the mixture was stirred at 20° C. for 8 hours under N₂.1-iodo-7-[4-(trifluoromethoxy)-phenyl]imidazo[1,5-a]pyridine (80.00 mg,197.96 umol, 1.00 eq) was added, then the mixture was stirred at 20° C.for 2 hours and at 90° C. for 10 hours. The mixture was then dilutedwith H₂O (10 mL) and extracted with EtOAc (30 mL×2). The combinedorganic phase was washed with water (10 mL×2) and brine (10 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product, whichwas purified by Prep-TLC (PET/EtOAc=3/1) to afford Compound 2 (18.93 mg,54.68 μmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ=8.17 (s, 1H), 8.09(dd, 1H), 7.80 (s, 1H), 7.66 (d, 2H), 7.35 (d, 2H), 7.01 (dd, 1H). LCMSR_(t)=1.268 min in 2.0 min chromatography, MS ESI calcd. for C₁₅H₉F₆N₂O[M+H]⁺ 347.1, found 346.8.

Example 3: Synthesis of Compound 3

Synthesis of A-7

A mixture of A-6 (1.00 g, 7.72 mmol, 1.00 eq),[4-(trifluoromethoxy)phenyl]boronic acid (2.07 g, 10.04 mmol, 1.30 eq),Pd(t-Bu₃P)₂ (197.27 mg, 386.00 μmol, 0.05 eq) and K₃PO₄ (3.28 g, 15.44mmol, 2.00 eq) in dioxane (50.00 mL) and H₂O (10.00 mL) was stirred at80° C. for 16 hours under N₂. The mixture was then concentrated to aresidue that was diluted with H₂O (50 mL) and extracted with EtOAc (100mL×3). The combined organic phase was washed with water (50 mL×2) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product, which was purified by silica gel (EtOAc in PE=15% to 30%to 50%) to afford A-7 (1.75 g, 6.86 mmol) as a solid. ¹H NMR (400 MHz,CDCl₃) δ=8.38 (d, 1H), 8.05 (d, 2H), 7.32 (d, 2H), 7.03 (d, 1H), 5.13(brs, 2H).

Synthesis of A-8

To a mixture of A-7 (1.50 g, 5.88 mmol, 1.00 eq), CH₂I₂ (7.87 g, 29.40mmol, 2.37 mL, 5.00 eq) and CuI (1.12 g, 5.88 mmol, 1.00 eq) in THF(30.00 mL) was added isoamyl nitrite (2.07 g, 17.64 mmol, 2.38 mL, 3.00eq) under N₂, and the mixture was stirred at 70° C. for 12 hours. Themixture was filtered through Celite, and the filtrate was concentratedto form a residue that was diluted with EtOAc (150 mL×2). The organicphase was washed with water (20 mL×2) and brine (20 mL), dried overNa₂SO₄, filtered and concentrated to give a crude product that waspurified by silica gel (EtOAc in PE=5% to 10% to 15%) to afford A-8(900.00 mg, 2.46 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ=8.49 (d,1H), 8.12 (d, 2H), 7.67 (d, 1H), 7.36 (d, 2H). LCMS R_(t)=0.925 min in1.5 min chromatography, MS ESI calcd. for C₁₁H₇F₃IN₂O [M+H]⁺ 366.9,found 366.8.

Synthesis of A-9

A mixture of A-8 (600.00 mg, 1.64 mmol, 1.00 eq), Zn(CN)₂ (384.90 mg,3.28 mmol, 2.00 eq), Pd₂(dba)₃ (150.09 mg, 164.00 μmol, 0.10 eq), Zn(10.72 mg, 164.00 μmol, 0.10 eq) and dppf (181.72 mg, 328.00 μmol, 0.20eq) in DMF (10.00 mL) was stirred at 100° C. for 32 hours. The mixturewas diluted with H₂O (30 mL) and extracted with EtOAc (100 mL×2). Thecombined organic phase was washed with water (20 mL×2) and brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct, which was purified by silica gel (EtOAc in PE=5% to 10% to 15%)to afford A-9 (350.00 mg, 1.26 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ=8.88 (d, 1H), 8.20 (d, 2H), 7.88 (d, 1H), 7.40 (d, 2H). LCMSR_(t)=0.901 min in 1.5 min chromatography, MS ESI calcd. for C₁₂H₇F₃N₃O[M+H]⁺ 266.0, found 265.9.

Synthesis of A-10

A mixture of A-9 (200.00 mg, 754.18 umol, 1.00 eq) and 10% Pd/C (200.00mg) in CF₃COOH (8.00 mL) was stirred under H₂ (15 psi) at 15° C. for 3hours. The mixture was filtered through Celite, the filtrateconcentrated, and the resulting residue was diluted with EtOAc (100 mL).The organic phase was washed with sat. Na₂CO₃ (20 mL) and brine (20 mL),dried over Na₂SO₄, filtered and concentrated to afford A-10 (200.00 mg,709.53 μmol) as an oil. LCMS R_(t)=0.782 min in 1.5 min chromatography,MS ESI calcd. for C₁₂H₁₁F₃N₃ [M+H]⁺ 270.1, found 269.9.

Synthesis of A-11

A mixture of A-11 (170.00 mg, 631.45 μmol, 1.00 eq) in HCOOH (8.00 mL)was stirred at 115° C. for 48 hours. The mixture was then concentratedto a residue, diluted with H₂O (15 mL) and sat.Na₂CO₃ (15 mL), andextracted with EtOAc (30 mL×2). The combined organic phase was washedwith water (10 mL×2) and brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to afford A-11 (210.00 mg, crude) as a solid. LCMSR_(t)=0.744 min in 1.5 min chromatography, MS ESI calcd. forC₁₃H₁₁F₃N₃O₂ [M+H]⁺ 298.1, found 297.9.

Synthesis of Compound 3

A mixture of A-11 (210.00 mg, 706.52 umol, 1.00 eq) in POCl₃ (4.00 mL)was stirred at 90° C. for 2 hours. The mixture was concentrated to aresidue, poured into ice-water (20 mL) basified with Na₂CO₃ (solid) topH˜9, and extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (10 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give a crude product that was purified byPrep-TLC (DCM/EtOAc=1/2) to afford Compound 3 (78.32 mg, 172.21 μmol) asa solid. ¹H NMR (400 MHz, CDCl₃) δ=8.28 (dd, 1H), 8.13-8.05 (m, 3H),7.69 (s, 1H), 7.35 (d, 2H), 7.07 (d, 1H). LCMS R_(t)=0.932 min in 2.0min chromatography, MS ESI calcd. for C₁₃H₉F₃N₃O [M+H]⁺ 280.1, found279.7.

Example 4: Synthesis of Compound 4

Synthesis of A-12

To a mixture of Compound 3 (180 mg, 644.66 μmol, 1.00 eq) and NaHCO₃(324.95 mg, 3.87 mmol, 6 eq) in H₂O (3 mL) and EtOH (6 mL) was added 12(327.24 mg, 1.29 mmol, 2 eq), and the mixture was stirred at 15° C. for16 hours. The mixture was quenched by saturated Na₂S₂O₃ (10 mL) and H₂O(20 mL) and extracted with EtOAc (50 mL×2). The combined organic phasewas washed with brine (15 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by Prep-TLC(PET/EtOAc=1/2) to afford A-12 (210 mg, 518.37 μmol) as a solid. ¹H NMR(400 MHz, CDCl₃) δ=8.24 (d, 1H), 8.17 (d, 2H), 8.12 (s, 1H), 7.36 (d,2H), 7.12 (d, 1H). LCMS R_(t)=0.871 min in 1.5 min chromatography, MSESI calcd. for C₁₃H₅F₃IN₃O [M+H]⁺ 406.0, found 405.8.

Synthesis of Compound 4

To a mixture of AgF (81.42 mg, 641.80 μmol, 2.60 eq) in DMF (6 mL) wasadded TMSCF₃ (112.32 mg, 789.90 μmol, 3.20 eq), and the mixture wasstirred at 20° C. for 1 hours. Cu (62.75 mg, 987.38 umol, 4.00 eq) wasadded, then the mixture was stirred at 20° C. for 5 hours under N₂,followed by addition of8-iodo-2-[4-(trifluoromethoxy)phenyl]imidazo[1,5-a]pyrimidine (100 mg,246.84 umol, 1.00 eq). The mixture was stirred at 20° C. for 2 hours andat 90° C. for 10 hours. The mixture was diluted with H₂O (15 mL) andextracted with EtOAc (50 mL×2). The combined organic phase was washedwith water (15 mL×2) and brine (15 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by Prep-TLC(PET/EtOAc=1/2) to afford Compound 4 (44.09 mg, 126.98 μmol) as a solid.¹H NMR (400 MHz, DMSO-d₆) δ=9.00 (d, 1H), 8.51 (s, 1H), 8.34 (d, 2H),7.72 (d, 1H), 7.58 (d, 2H). LCMS R_(t)=1.220 min in 2.0 minchromatography, MS ESI calcd. for C₁₄H₈F₆N₃O [M+H]⁺ 348.0, found 347.8.

Example 5: Synthesis of Compound 5

To a mixture of 2-methyl-4-(trifluoromethoxy)aniline (4 g, 20.93 mmol),TBAB (16.86 g, 52.31 mmol) and TsOH·H₂O (5.17 g, 27.2 mmol) in MeCN (40mL) was added isopentyl nitrite (2.94 g, 25.11 mmol) and CuBr₂ (467.38mg, 2.09 mmol), then the mixture was stirred at 20° C. for 12 hours. Themixture was diluted with H₂O (100 mL), and the mixture was extractedwith DCM (100 mL×2). The combined organic phase was washed with water(40 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby silica gel column (EtOAc in PE=0% to 2%) to give1-bromo-2-methyl-4-(trifluoromethoxy)benzene (4 g, 75% yield) as an oil.¹H NMR (400 MHz, CDCl₃) δ_(H) 7.54 (d, 1H), 7.11 (s, 1H), 6.94 (dd, 1H),2.42 (s, 3H).

A mixture of 1-bromo-2-methyl-4-(trifluoromethoxy)benzene (4 g, 15.68mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(11.95 g, 47.05 mmol), Pd(dppf)Cl₂·CH₂Cl₂ (1.28 g, 1.57 mmol) and KOAc(3.08 g, 31.37 mmol) in 1,4-dioxane (100 mL) was stirred at 90° C. for16 hours under N₂. After cooling to r.t., the mixture was concentrated.The residue was diluted with H₂O (50 mL), and the mixture was extractedwith EtOAc (150 mL×2). The combined organic phase was washed with water(50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby silica gel column (EtOAc in PE=0% to 1%) to give4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(4.4 g, 93% yield) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H) 7.79 (d,1H), 7.04-6.98 (m, 2H), 2.56 (s, 3H), 1.35 (s, 12H).

A mixture of 3,5-dichloropyridazine (500 mg, 3.36 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(861.81 mg, 2.85 mmol), Pd(t-Bu₃P)₂ (171.52 mg, 0.34 mmol) and K₃PO₄(1.43 g, 6.71 mmol) in 1,4-Dioxane (30 mL) and Water (6 mL) was stirredat 75° C. for 16 hours under N₂. After cooling to r.t., the mixture wasconcentrated to the residue. The residue was diluted with H₂O (30 mL),and the mixture was extracted with EtOAc (50 mL×2). The combined organicphase was washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by silica gel column (EtOAc in PE=0% to 10% to 20%)to give the product (510 mg, 1.70 mmol, 51% yield) as a solid. ¹H NMR(400 MHz, DMSO-d₆) δ=9.37 (d, 1H), 8.08 (d, 1H), 7.54 (d, 1H), 7.45 (s,1H), 7.38 (d, 1H), 2.35 (s, 3H). LCMS R_(t)=0.832 min in 1.5 minchromatography, MS ESI calcd. for C₁₂H₉ClF₃N₂O [M+H]⁺ 289.0, found288.9.

A mixture of Zn(CN)₂ (549.21 mg, 4.68 mmol), Pd₂(dba)₃ (142.76 mg, 0.16mmol), dppf (259.28 mg, 0.47 mmol), Zn (15.29 mg, 0.23 mmol) and3-chloro-5-[2-methyl-4-(trifluoromethoxy)phenyl]pyridazine (450 mg, 1.56mmol) in DMF (20 mL) was stirred at 100° C. for 2 hours under N₂. Aftercooling to r.t., the mixture was diluted with H₂O (30 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by silica gel column (EtOAc in PE=0% to 10% to 20%) to givethe product (380 mg, 1.32 mmol, 84% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ=9.38 (d, 1H), 7.82 (d, 1H), 7.31-7.27 (m, 1H), 7.26-7.22 (m,2H), 2.37 (s, 3H). LCMS R_(t)=0.815 min in 1.5 min chromatography, MSESI calcd. for C₁₃H₉F₃N₃O [M+H]⁺ 280.1, found 279.9.

To a mixture of5-[2-methyl-4-(trifluoromethoxy)phenyl]pyridazine-3-carbonitrile (60 mg,0.21 mmol) in Ethyl acetate (1 mL) and Acetic acid (1 mL) was added 10%Pd/C (20 mg, wt), then the mixture was stirred under H₂ (15 psi) at 20°C. for 1 hour. The mixture was filtered through Celite, and the filtratewas concentrated to the crude product (70 mg, 0.20 mmol) as an oil,which was used directly without any further purification. LCMSR_(t)=0.678 min in 1.5 min chromatography, MS ESI calcd. for C₁₃H₁₃F₃N₃O[M+H]⁺ 284.1, found 283.9.

A mixture of(5-(2-methyl-4-(trifluoromethoxy)phenyl)pyridazin-3-yl)methanamineacetate (70 mg, 0.20 mmol) in formic acid (0.5 mL, 13.25 mmol) wasstirred at 100° C. for 2 hours. After cooling to r.t., the mixture wasconcentrated to the crude product (80 mg, 0.19 mmol) as an oil. LCMSR_(t)=0.738 min in 1.5 min chromatography, MS ESI calcd. forC₁₄H₁₃F₃N₃O₂ [M+H]⁺ 312.1, found 311.9.

A mixture ofN-((5-(2-methyl-4-(trifluoromethoxy)phenyl)pyridazin-3-yl)methyl)formamideformate (80 mg, 0.22 mmol) in POCl₃ (1 mL, 10.73 mmol) was stirred at100° C. for 1 hour. After cooling to r.t., the mixture was poured intoice-water (15 mL) and the mixture was basified with Na₂CO₃ (solid) topH˜9 and extracted with EtOAc (20 mL×2). The combined organic phase waswashed with water (10 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (PE/EtOAc=2/1) to give the product (26.75 mg,0.09 mmol, 41% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ=8.51 (s,1H), 8.07 (d, 1H), 7.73 (d, 1H), 7.55 (s, 1H), 7.29 (d, 1H), 7.21-7.14(m, 2H), 2.37 (s, 3H). LCMS R_(t)=1.029 min in 2.0 min chromatography,MS ESI calcd. for C₁₄H₁₁F₃N₃O [M+H]⁺ 294.1, found 293.9.

Example 6: Synthesis of Compound 6

To a mixture of3-[2-methyl-4-(trifluoromethoxy)phenyl]imidazo[1,5-b]pyridazine (100 mg,0.34 mmol) in DMF (5 mL) was added 12 (216.38 mg, 0.85 mmol) and KOH(66.97 mg, 1.19 mmol), then the mixture was stirred at 20° C. for 16hours. The mixture was quenched with H₂O (30 mL), and the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith water (20 mL×2) and brine (20 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-TLC (PET/EtOAc=3/1) to give the product (80 mg, 0.19 mmol, 55%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ=8.48 (s, 1H), 8.07 (d, 1H),7.56 (d, 1H), 7.31 (d, 1H), 7.22-7.15 (m, 2H), 2.38 (s, 3H). LCMSR_(t)=0.895 min in 1.5 min chromatography, MS ESI calcd. forC₁₄H₁₀F₃IN₃O [M+H]⁺ 420.0, found 419.9.

To a mixture of fluorosilver (920 mg, 7.25 mmol) in DMF (50 mL) wasadded trimethyl(trifluoromethyl)silane (1.34 g, 9.43 mmol) under N₂ at20° C., then the mixture was stirred at 20° C. for 2 hours. To themixture was added copper (737.33 mg, 11.6 mmol), then the mixture wasstirred at 20° C. for 6 hours under N₂. CuCF₃ (961.19 mg, 7.25 mmol,100% yield) was obtained as a solution in DMF (0.145 M, 50 mL), whichwas used next step directly. A mixture of5-iodo-3-[2-methyl-4-(trifluoromethoxy)phenyl]imidazo[1,5-b]pyridazine(80 mg, 0.19 mmol) in CuCF₃ in DMF (13 mL, 1.89 mmol) was stirred at 20°C. for 2 hours and 90° C. for 10 hours in 20 m L sealed tube under N₂.After cooling to r.t., the mixture was diluted with H₂O (40 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (30 mL×2) and brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (PET/EtOAc=3/1) to give the product (53.07 mg,0.1469 mmol, 78% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ=8.53 (s,1H), 8.22 (d, 1H), 7.91 (s, 1H), 7.32 (d, 1H), 7.24-7.17 (m, 2H), 2.38(s, 3H). LCMS R_(t)=1.293 min in 2.0 min chromatography, MS ESI calcd.for C₁₅H₁₀F₆N₃O [M+H]⁺ 362.1, found 362.0.

Example 7: Synthesis of Compound 7

A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (1.5 g, 7.69mmol), [4-(trifluoromethoxy)phenyl]boronic acid (1.35 g, 6.54 mmol),Pd(dppf)Cl₂ (843.97 mg, 1.15 mmol) and K₂CO₃ (2.13 g, 15.38 mmol) in1,4-Dioxane (60 mL) and Water (15 mL) was stirred at 75° C. for 3 hoursunder N₂. After cooling to r.t., the mixture was concentrated to aresidue. The residue was diluted with H₂O (50 mL), and the mixture wasextracted with EtOAc (100 mL×2). The combined organic phase was washedwith water (50 mL) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 1% to 2%) togive the product (2500 mg, 4.59 mmol, 60% yield) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H)=8.12 (d, 2H), 7.38-7.32 (m, 3H), 2.65 (s, 3H). LCMSRt=0.97 min in 1.5 min chromatography, MS ESI calcd. for C₁₂H₉ClF₃N₂OS[M+H]⁺ 321.0, found 320.9.

A mixture of4-chloro-2-methylsulfanyl-6-[4-(trifluoromethoxy)phenyl]pyrimidine (2 g,6.2 mmol), dicyanozinc (1.46 g, 12.4 mmol), Zn (60.79 mg, 0.93 mmol),Pd₂(dba)₃ (567.56 mg, 0.62 mmol) and dppf (859 mg, 1.55 mmol) in DMF (30mL) was stirred at 95° C. for 2 hours under N₂. After cooling to r.t.,the mixture was diluted with H₂O (60 mL), and the mixture was extractedwith EtOAc (100 mL×2). The combined organic phase was washed with water(50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 1% to 3%) togive the product (1300 mg, 3.11 mmol, 50% yield) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H)=8.15 (d, 2H), 7.64 (s, 1H), 7.38 (d, 2H), 2.66 (s,3H). LCMS R_(t)=0.94 min in 1.5 min chromatography, MS ESI calcd. forC₁₃H₉F₃N₃OS [M]⁺ 312.0, found 311.9.

To a mixture of2-methylsulfanyl-6-[4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile(600 mg, 1.93 mmol) and NiCl₂.6H₂O (680 mg, 2.86 mmol) in Methanol (10mL) was added NaBH₄ (291.67 mg, 7.71 mmol) at 10° C., then the mixturewas stirred at 25° C. for 0.5 hour. The mixture was quenched by H₂O (50mL), and the mixture was extracted with EtOAc (100 mL×2). The combinedorganic phase was washed with water (50 mL×2) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product (550mg, 0.58 mmol) as a solid. LCMS R_(t)=0.75 min in 1.5 minchromatography, MS ESI calcd. for C₁₃H₁₃F₃N₃OS [M+H]⁺ 316.1, found315.9.

A mixture of[2-methylsulfanyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanamine(550 mg, 1.74 mmol) in formic acid (30 g, 651.75 mmol) was stirred at105° C. for 12 hours. After cooling to r.t., the mixture wasconcentrated to give the crude product (600 mg, 0.45 mmol) as an oil.The crude product was used in next step without further purification.LCMS Rt=0.82 min in 1.5 min chromatography, MS ESI calcd. forC₁₄H₁₃F₃N₃O₂S [M+H]⁺ 344.1, found 343.9.

To a mixture ofN-[[2-methylsulfanyl-6-[4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl]formamide(550 mg, 1.6 mmol) in 1,4-Dioxane (30 mL) was added POCl₃ (0.45 mL, 4.81mmol), then the mixture was stirred at 90° C. for 1 hours. After coolingto r.t., the mixture was poured into ice-water (30 mL), and the mixturewas basified with Na₂CO₃ (solid) to pH˜9 and extracted with EtOAc (50mL×2). The combined organic phase was washed with water (20 mL×2) andbrine (20 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 20% to 60%) to give the product (140 mg,0.27 mmol, 17% yield) as an oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=8.50(s, 1H), 8.26 (d, 2H), 8.05 (s, 1H), 7.57 (s, 1H), 7.48 (d, 2H), 2.87(s, 3H). LCMS R_(t)=0.86 min in 1.5 min chromatography, MS ESI calcd.for C₁₄H₁₁F₃N₃OS [M+H]⁺ 326.1, found 325.9.

To a mixture of5-methylsulfanyl-7-[4-(trifluoromethoxy)phenyl]imidazo[1,5-c]pyrimidine(40 mg, 0.08 mmol) and 10% Pd/C (40 mg) in THE (2 mL) was added Et₃SiH(500 mg, 4.3 mmol) at 10° C., then the mixture was stirred at 10° C. for0.5 hour. After cooling to r.t., the mixture was filtered throughCelite, and the filtrate was concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 20% to 50%) to give the impure product. The impure productwas purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product(5.19 mg, 0.02 mmol, 24% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆)δ_(H)=9.36 (s, 1H), 8.58 (s, 1H), 8.24-8.15 (m, 3H), 7.53-7.42 (m, 3H).LCMS R_(t)=1.84 min in 3.0 min chromatography, MS ESI calcd. forC₁₃H₉F₃N₃O [M+H]⁺ 280.1, found 280.0.

Example 8: Synthesis of Compound 8

To a mixture of 7-[4-(trifluoromethoxy)phenyl]imidazo[1,5-c]pyrimidine(40 mg, 0.12 mmol) in DMF (4 mL) was added 12 (60 mg, 0.24 mmol) and KOH(20 mg, 0.36 mmol), then the mixture was stirred at 25° C. for 2 hours.The mixture was diluted with H₂O (10 mL), and the mixture was extractedwith EtOAc (20 mL×2). The combined organic phase was washed with water(10 mL×2) and brine (10 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby Prep-TLC (silica gel, PE:EtOAc=3:1) to give the product (20 mg, 0.05mmol, 40% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.88 (d, 1H),8.27 (s, 1H), 8.07 (d, 2H), 7.55 (s, 1H), 7.33 (d, 2H). LCMS R_(t)=2.00min in 3 min chromatography, MS ESI calcd. for C₁₃H₈F₃IN₃O [M+H]⁺ 406.0,found 405.9.

To a mixture of AgF (114 mg, 0.90 mmol) in DMF (6 mL) was addedtrimethyl(trifluoromethyl)silane (147 mg, 1.03 mmol), then the mixturewas stirred at 20° C. for 3 hours. To the mixture was added Cu (97 mg,1.53 mmol), then the mixture was stirred at 20° C. for 5 hours. To themixture was added1-iodo-7-[4-(trifluoromethoxy)phenyl]imidazo[1,5-c]pyrimidine (20 mg,0.05 mmol), then the mixture was stirred at 20° C. for 1 hour and 90° C.for 12 hours. After cooling to r.t., the mixture was diluted with H₂O(15 mL), and the mixture was extracted with EtOAc (30 mL×2). Thecombined organic phase was washed with water (20 mL×2) and brine (20mL), dried over Na₂SO₄, filtered and concentrated to give the crudeproduct. The crude product was purified by Prep-TLC (silica gel,PE:EtOAc=3:1) to give the product (8.52 mg, 0.02 mmol, 48% yield) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=9.02 (d, 1H), 8.30 (s, 1H), 8.08(d, 2H), 7.86 (s, 1H), 7.35 (d, 2H). LCMS R_(t)=1.34 min in 2.0 minchromatography, MS ESI calcd. for C₁₄H₈F₆N₃O [M+H]⁺ 348.1, found 347.8.

Example 9: Synthesis of Compound 9

A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (3 g, 15.38 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(4.18 g, 13.84 mmol), Pd(dppf)Cl₂ (1.69 g, 2.31 mmol) and K₂CO₃ (4.25 g,30.76 mmol) in 1,4-Dioxane (120 mL) and Water (30 mL) was stirred at 70°C. for 2 hours under N₂. After cooling to r.t., the mixture wasconcentrated to the residue. The residue was diluted with H₂O (50 mL),and the mixture was extracted with EtOAc (100 mL×2). The combinedorganic phase was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 4% to 8%) to give the product (4300 mg, 8.01 mmol) as anoil. LCMS R_(t)=1.00 min in 1.5 min chromatography, MS ESI calcd. forC₁₃H₁₁ClF₃N₂OS [M+H]⁺ 335.0, found 335.2.

A mixture of4-chloro-2-methylsulfanyl-6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrimidine(4.3 g, 12.85 mmol), dicyanozinc (3.02 g, 25.69 mmol), Zn (126 mg, 1.93mmol), Pd₂(dba)₃ (1.18 g, 1.28 mmol) and dppf (1.78 g, 3.21 mmol) in DMF(50 mL) was stirred at 90° C. for 2 hours under N₂. After cooling tor.t., the mixture was diluted with H₂O (80 mL), and the mixture wasextracted with EtOAc (150 mL×2). The combined organic phase was washedwith water (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) togive the product (2900 mg, 5.79 mmol) as a solid. LCMS R_(t)=0.96 min in1.5 min chromatography, MS ESI calcd. for C₁₄H₁₁F₃N₃OS [M+H]⁺ 326.0,found 325.9.

To a mixture of2-methylsulfanyl-6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrimidine-4-carbonitrile(2.9 g, 8.91 mmol) and NiCl₂.6H₂O (3.14 g, 13.23 mmol) in Methanol (30mL) was added NaBH₄ (1.35 g, 35.66 mmol) at 10° C., then the mixture wasstirred at 25° C. for 0.5 hour. The mixture was quenched by H₂O (50 mL),and the mixture was extracted with EtOAc (150 mL×2). The combinedorganic phase was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product (2900mg, 2.75 mmol) as an oil. LCMS Rt=0.77 min in 1.5 min chromatography, MSESI calcd. for C₁₄H₁₅F₃N₃OS [M+H]⁺ 330.1, found 329.9.

A mixture of[2-methylsulfanyl-6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methanamine(2.9 g, 8.81 mmol) in formic acid (50 g, 1086.3 mmol) was stirred at105° C. for 12 hours. After cooling to r.t., the mixture wasconcentrated to give the crude product (3000 mg, 8.39 mmol) as an oil,which was used next step without further purification. LCMS R_(t)=0.84min in 1.5 min chromatography, MS ESI calcd. for C₁₅H₁₅F₃N₃O₂S [M+H]⁺358.1, found 357.9.

To a mixture ofN-[[2-methylsulfanyl-6-[2-methyl-4-(trifluoromethoxy)phenyl]pyrimidin-4-yl]methyl]formamide(3 g, 8.4 mmol) in 1,4-Dioxane (50 mL) was added POCl₃ (1.57 mL, 16.79mmol), then the mixture was stirred at 90° C. for 1 hour. After coolingto r.t., the mixture was poured into ice-water (100 mL) and the mixturewas basified with Na₂CO₃ (solid) to pH˜9 and extracted with EtOAc (150mL×2). The combined organic phase was washed with water (50 mL×2) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 20% to 50%) to give the product (510 mg,1.23 mmol, 15% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.20 (s,1H), 8.54-7.47 (m, 2H), 7.21 (s, 1H), 7.17-7.11 (m, 2H), 2.79 (s, 3H),2.49 (s, 3H). LCMS R_(t)=0.88 min in 1.5 min chromatography, MS ESIcalcd. for C₁₅H₁₃F₃N₃OS [M+H]⁺ 340.1, found 339.9.

To a mixture of5-methylsulfanyl-7-[2-methyl-4-(trifluoromethoxy)phenyl]imidazo[1,5-c]pyrimidine(500 mg, 1.47 mmol) and 10% Pd/C (500 mg) in THE (25 mL) was addedEt₃SiH (10 g, 86 mmol) at 15° C., then the mixture was stirred at 15° C.for 2 hours. The mixture was filtered through Celite, and the filtratewas concentrated to the crude product. The crude product was purified byflash chromatography on silica gel (EtOAc in PE=0% to 50% to 100%) togive the product (300 mg, 0.86 mmol) as a solid. LCMS R_(t)=1.85 min in3.0 min chromatography, MS ESI calcd. for C₁₄H₁₁F₃N₃O [M+H]⁺ 294.1,found 294.1.

The impure product was purified by Prep-TLC (silica gel, PE:EtOAc=1:2)to give the product (10.8 mg, 36.5 μmol) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.95 (s, 1H), 8.30 (s, 1H), 7.53-7.46 (m, 2H), 7.39 (s,1H), 7.19-7.11 (m, 2H), 2.46 (s, 3H). LCMS R_(t)=1.85 min in 3.0 minchromatography, MS ESI calcd. for C₁₄H₁₁F₃N₃O [M+H]⁺ 294.1, found 294.1.

Example 10: Synthesis of Compound 10

Synthesis of A-19b: To a suspension of NaH (2.94 g, 73.56 mmol) in THE(50 mL) was added 2,2,2-trifluoroethanol (7.36 g, 73.56 mmol) slowly at20° C., and the mixture was stirred for 1 hour.5-chloro-2,3-difluoro-pyridine (10 g, 66.88 mmol) was then added, andthe mixture was stirred at 20° C. for another 4 hours. The mixture wasquenched with sat.NH₄Cl (50 mL) and extracted with EtOAc (100 mL×2). Thecombined organic phase was washed with brine (50 mL), dried over Na₂SO₄,filtered and concentrated to afford A-19b (15000 mg, 65.34 mmol) as anoil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.83 (d, 1H), 7.38 (dd, 1H), 4.73 (q,2H).

Synthesis of A-19c: A mixture of A-19b (8 g, 34.85 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(26.55 g, 104.55 mmol), K₃PO₄ (14.79 g, 69.7 mmol), SPhos (4.29 g, 10.45mmol) and Pd(OAc)₂ (782.4 mg, 3.48 mmol) in 1,4-dioxane (250 mL) wasstirred at 85° C. for 16 hours. After cooling to room temperature, themixture was filtered through Celite and eluted with EtOAc (50 mL×2). Thefiltrate was concentrated and diluted with EtOAc (200 mL), washed withwater (100 mL×2) and brine (100 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product, which was purified by flashchromatography on silica gel (EtOAc in PE=0 to 10% to 40%) to affordA-19c (3 g, 4.6021 mmol) as an oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.26(d, 1H), 7.72 (dd, 1H), 4.87 (q, 2H), 1.35 (s, 12H). LCMS R_(t)=0.94 minusing Method B, MS ESI calcd. for C₁₃H₁₇BF₄NO₃ [M+H]⁺ 322.1, found322.3.

A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (3 g, 15.38 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(8.39 g, 26.14 mmol), Pd(dppf)Cl₂ (1.69 g, 2.31 mmol) and K₂CO₃ (4.25 g,30.76 mmol) in 1,4-Dioxane (120 mL) and Water (30 mL) was stirred at 70°C. for 2 hours under N₂. After cooling to r.t., the mixture wasconcentrated to a residue. The residue was diluted with H₂O (50 mL), andthe mixture was extracted with EtOAc (100 mL×2). The combined organicphase was washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 5% to 10%) to give the product (5000 mg, 9.52 mmol) as an oil.LCMS R_(t)=0.96 min in 1.5 min chromatography, MS ESI calcd. forC₁₂H₉ClF₄N₃OS [M+H]⁺ 354.0, found 353.8.

A mixture of4-chloro-6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidine(5 g, 14.14 mmol), dicyanozinc (3.32 g, 28.27 mmol), Zn (138.65 mg, 2.12mmol), Pd₂(dba)₃ (1.29 g, 1.41 mmol) and dppf (1.96 g, 3.53 mmol) in DMF(50 mL) was stirred at 90° C. for 2 hours under N₂. After cooling tor.t., the mixture was diluted with H₂O (80 mL), and the mixture wasextracted with EtOAc (150 mL×2). The combined organic phase was washedwith water (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) togive the product (3200 mg, 4.46 mmol) as an oil. LCMS R_(t)=0.93 min in1.5 min chromatography, MS ESI calcd. for C₁₃H₉F₄N₄₀S [M+H]⁺ 345.0,found 344.9.

To a mixture of6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidine-4-carbonitrile(3.2 g, 9.29 mmol) and NiCl₂.6H₂O (3.31 g, 13.94 mmol) in methanol (30mL) was added NaBH₄ (0.88 g, 23.24 mmol) at 10° C., then the mixture wasstirred at 25° C. for 0.5 hour. The mixture was quenched by H₂O (50 mL),and the mixture was extracted with EtOAc (150 mL×2). The combinedorganic phase was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product (3000mg, 0.93 mmol) as an oil. LCMS R_(t)=0.75 min in 1.5 min chromatography,MS ESI calcd. for C₁₃H₁₃F₄N₄OS [M+H]⁺ 349.1, found 348.9.

A mixture of[6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methanamine(3 g, 8.61 mmol) in formic acid (50 g, 1086.3 mmol) was stirred at 105°C. for 12 hours. After cooling to r.t., the mixture was concentrated togive the crude product (3000 mg, 7.97 mmol) as an oil. LCMS R_(t)=0.82min in 1.5 min chromatography, MS ESI calcd. for C₁₄H₁₃F₄N₄O₂S [M+H]⁺377.1, found 376.9.

To a mixture ofN-[[6-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methyl]formamide(3 g, 7.97 mmol) in 1,4-Dioxane (50 mL) was added POCl₃ (1.49 mL, 15.94mmol), then the mixture was stirred at 90° C. for 1 hour. After coolingto r.t., the mixture was poured into ice-water (100 mL) and the mixturewas basified with Na₂CO₃ (solid) to pH˜9, and extracted with EtOAc (150mL×2). The combined organic phase was washed with water (50 mL×2) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 60%) to give the product (370 mg,0.84 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.59 (d, 1H), 8.19(s, 1H), 8.06 (dd, 1H), 7.59-7.48 (m, 2H), 4.95-4.87 (m, 2H), 2.88 (s,3H). LCMS R_(t)=0.85 min in 1.5 min chromatography, MS ESI calcd. forC₁₄H₁₁F₄N₄OS [M+H]⁺ 359.1, found 358.9.

To a mixture of7-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-5-methylsulfanyl-imidazo[1,5-c]pyrimidine(350 mg, 0.80 mmol) and 10% Pd/C (350 mg) in THE (25 mL) was addedEt₃SiH (8 g, 68.8 mmol) at 15° C., then the mixture was stirred at 15°C. for 2 hours. The mixture was filtered through Celite, and thefiltrate was concentrated to the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 50% to100%) to give the product (150 mg, 0.37 mmol) as a solid. LCMSR_(t)=1.79 min in 3.0 min chromatography, MS ESI calcd. for C₁₃H₉F₄N₄₀[M+H]⁺ 314.1, found 313.1.

The impure product was purified by Prep-TLC (silica gel, PE:EtOAc=1:2)to give the product (10.36 mg, 32.0 μmol) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.95 (s, 1H), 8.53 (d, 1H), 8.29 (s, 1H), 8.05 (dd, 1H),7.69 (s, 1H), 7.54 (s, 1H), 4.91 (q, 2H). LCMS R_(t)=1.79 min in 3.0 minchromatography, MS ESI calcd. for C₁₃H₉F₄N₄O [M+H]⁺ 313.1, found 313.1.

Example 11: Synthesis of Compound 11

To a solution of (R,R)—Co(salen) (550 mg, 0.91 mmol) in Toluene (10 mL)was added AcOH (0.5 5 mL, 9.6 mmol), and the mixture was stirred at 15°C. open to air for 1 hour. Then the mixture was concentrated, and thebrown residue was dissolved in 2-(trifluoromethyl)oxirane (50 g, 446.23mmol). To the mixture was added H₂O (4.4 mL, 244.44 mmol) at 0° C. andthe mixture was stirred at 15° C. for 56 hours. The mixture wasdistilled at ˜15° C. under reduced vacuum (˜100 mm Hg), and the productwas collected with a cold trap (−78° C.) to give the product (18000 mg,160.64 mmol, 36% yield) as colorless liquid. The product was ring-openedwith BnNH₂ (1 eq), and the resulted solid triturated from n-hexane andanalyzed by SFC to show the ee % was about 86%. Method: Column: ChiralCD-Ph 250×4.6 mm I.D., 5 μm; Mobile phase: from 10% to 80% of B in A; A:Water with 0.069% TFA B: Acetonitrile; Flow rate: 0.8 mL/min; ColumnTemperature: 30° C. ¹H NMR (400 MHz, CDCl₃) δ_(H)=3.47-3.40 (m, 1H),3.02-2.97 (m, 1H), 2.96-2.91 (m, 1H).

To a mixture of (2S)-2-(trifluoromethyl)oxirane (18 g, 160.64 mmol) inEther (150 mL) was added LiAlH₄ (3.05 g, 80.32 mmol) at 0° C., then themixture was stirred at 15° C. for 1 hours. After cooling to 0° C., themixture was quenched with water (4 mL), and the mixture was stirred at20° C. for 30 minutes. The mixture was filtered through Celite, elutedwith Et₂O (100 mL×3), and the organic phase was dried over Na₂SO₄,filtered and concentrated to give the crude product (8000 mg, 70.13mmol) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=6.03 (d, 1H),4.14-3.97 (m, 1H), 1.20 (d, 3H).

To a solution of (2S)-1,1,1-trifluoropropan-2-ol (8 g, 70.13 mmol) inTHE (100 mL) was added NaH (2.81 g, 70.13 mmol) at 0° C., and themixture was stirred at 0° C. for 30 mins. Then to the mixture was added5-bromo-2,3-difluoro-pyridine (13.6 g, 70.13 mmol), and the mixture wasstirred at 15° C. for 3 hours. The mixture was diluted with sat. NH₄Cl(50 mL) and extracted with EtOAc (100 mL×2). The combined organic phasewas washed with H₂O (30 mL) and brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product (18000 mg, 62.49mmol) as an oil.

A brown mixture of5-bromo-3-fluoro-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (3 g,10.42 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(7.93 g, 31.25 mmol), KOAc (3.07 g, 31.25 mmol) and Pd(dppf)Cl₂ (1.14 g,1.56 mmol) in 1,4-Dioxane (150 mL) was stirred at 90° C. for 16 hours.After cooling to r.t., the mixture was concentrated to give the crudeproduct. The crude product was diluted with PE (200 mL), filteredthrough silica gel and eluted with PE (150 mL×2). The filtrate wasconcentrated to give the crude product (5000 mg, 14.92 mmol, crude) asan oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.17 (d, 1H), 7.62 (dd, 1H),5.89-5.72 (m, 1H), 1.46 (d, 3H), 1.26 (s, 12H).

A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (3 g, 15.38 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(4.64 g, 13.84 mmol), Pd(dppf)Cl₂ (1.69 g, 2.31 mmol) and K₂CO₃ (4.25 g,30.76 mmol) in 1,4-Dioxane (120 mL) and Water (30 mL) was stirred at 70°C. for 2 hours under N₂. After cooling to r.t., the mixture wasconcentrated to a residue. The residue was diluted with H₂O (50 mL), andthe mixture was extracted with EtOAc (100 mL×2). The combined organicphase was washed with water (50 mL) and brine (50 mL), dried overNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 5% to 10%) to give the product (3.3 g, 6.27 mmol) as an oil.LCMS R_(t)=1.05 min in 1.5 min chromatography, MS ESI calcd. forC₁₃H₁₁ClF₄N₃OS [M+H]⁺ 368.0, found 367.9.

A mixture of4-chloro-6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidine(3.3 g, 8.97 mmol), dicyanozinc (2.11 g, 17.95 mmol), Zn (88.02 mg, 1.35mmol), Pd₂(dba)₃ (821.72 mg, 0.90 mmol) and dppf (1.24 g, 2.24 mmol) inDMF (50 mL) was stirred at 90° C. for 2 hours under N₂. After cooling tor.t., the mixture was diluted with H₂O (80 mL), and the mixture wasextracted with EtOAc (150 mL×2). The combined organic phase was washedwith water (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) togive the product (1.8 g, 3.47 mmol) as an oil. LCMS R_(t)=0.97 min in1.5 min chromatography, MS ESI calcd. for C₁₄H₁₁F₄N₄OS [M+H]⁺ 359.1,found 358.9.

To a mixture of6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidine-4-carbonitrile(1.8 g, 5.02 mmol) and NiCl₂.6H₂O (1.5 g, 6.31 mmol) in methanol (30 mL)was added NaBH₄ (400 mg, 10.57 mmol) at 10° C., then the mixture wasstirred at 25° C. for 0.5 hour. The mixture was quenched by H₂O (50 mL),and the mixture was extracted with EtOAc (150 mL×2). The combinedorganic phase was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product (1.8 g)as an oil, which was used directly without any further purification.LCMS R_(t)=0.77 min in 1.5 min chromatography, MS ESI calcd. forC₁₄H₁₅F₄N₄OS [M+H]⁺ 363.1, found 363.0.

A mixture of[6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methanamine(1.8 g, 4.97 mmol) in formic acid (40 g, 869 mmol) was stirred at 105°C. for 12 hours. After cooling to r.t., the mixture was concentrated togive the crude product (1.8 g) as an oil, which was used next stepwithout further purification. LCMS R_(t)=0.85 min in 1.5 minchromatography, MS ESI calcd. for C₁₅H₁₅F₄N₄O₂S [M+H]⁺ 391.1, found391.0.

To a mixture ofN-[[6-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methyl]formamide(1.8 g, 4.61 mmol) in 1,4-Dioxane (50 mL) was added POCl₃ (0.86 mL, 9.22mmol), then the mixture was stirred at 90° C. for 1 hour. After coolingto r.t., the mixture was poured into ice-water (100 mL) and the mixturewas basified with Na₂CO₃ (solid) to pH˜9 and extracted with EtOAc (150mL×2). The combined organic phase was washed with water (50 mL×2) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 60%) to give the product (290 mg,417.2 μmol) as a solid. LCMS R_(t)=0.89 min in 1.5 min chromatography,MS ESI calcd. for C₁₅H₁₃F₄N₄OS [M+H]⁺ 373.1, found 372.9.

To a mixture of7-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methylsulfanyl-imidazo[1,5-c]pyrimidine(290 mg, 0.78 mmol) and 10% Pd/C (300 mg, 0.78 mmol) in THE (20 mL) wasadded Et₃SiH (7.52 g, 64.66 mmol) at 15° C., then the mixture wasstirred at 15° C. for 2 hours. The mixture was filtered through Celiteand the filtrate was concentrated to the crude product. The crudeproduct was purified by flash chromatography on silica gel (EtOAc inPE=0% to 50% to 100%) to give the impure product (70 mg) as a solid.

The impure product (20 mg) was purified by Prep-TLC (PE:EtOAc=1:3) togive the product (6.61 mg, 19.4 μmol) as a solid. ¹H NMR (400 MHZ,CDCl₃+D₂O) δ_(H)=8.95 (s, 1H), 8.52 (d, 1H), 8.29 (s, 1H), 8.03 (dd,1H), 7.67 (s, 1H), 7.53 (s, 1H), 5.89 (td, 1H), 1.58 (d, 3H). LCMSR_(t)=1.88 min in 3.0 min chromatography, MS ESI calcd. for C₁₄H₁₁F₄N₄O[M+H]⁺ 327.1, found 327.0.

Example 12: Synthesis of Compound 12

To a mixture of (S,S)—Co(salen) (107.76 mg, 0.18 mmol) in Toluene (3 mL)was added AcOH (0.11 mL, 1.87 mmol). The mixture was stirred at 20° C.for 30 minutes. The solution was concentrated in vacuum to give a crudebrown solid. The resulting catalyst residue was dissolved in2-(trifluoromethyl)oxirane (10 g, 89.25 mmol). To the mixture was addedH₂O (803.66 mg, 44.6 2 mmol) at 0° C., then the mixture was stirred at20° C. for 48 hours. The mixture was distilled at ˜15° C. under reducedvacuum (˜100 mm Hg), and the product was collected with a cold trap(−78° C.) to give (2R)-2-(trifluoromethyl)oxirane (3700 mg, 33.02 mmol,37% yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=3.49-3.39 (m,1H), 3.03-2.97 (m, 1H), 2.96-2.90 (m, 1H).

To a mixture of (2R)-2-(trifluoromethyl)oxirane (2 g, 17.85 mmol) inEther (30 mL) was added LiAlH₄ (338.69 mg, 8.92 mmol) at 0° C., then themixture was stirred at 20° C. for 2 hours. After cooling to 0° C., themixture was quenched with water (0.64 g), the mixture was stirred at 20°C. for 30 minutes. The mixture was filtered through Celite, eluted withEt₂O (30 mL×2), the organic phase was dried over Na₂SO₄, filtered andconcentrated to give the crude product (1100 mg, 9.64 mmol) as acolorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ_(H)=6.03 (d, 1H), 4.16-3.99(m, 1H), 1.20 (d, 3H).

To a solution of (2R)-1,1,1-trifluoropropan-2-ol (1.10 g, 9.64 mmol) inTHE (30 mL) was added NaH (490.93 mg, 12.27 mmol) at 0° C., and themixture was stirred at 0° C. for 30 mins. Then to the mixture was added5-bromo-2,3-difluoro-pyridine (1.70 g, 8.77 mmol), and the mixture wasstirred at 20° C. for 2 hours. The mixture was quenched with sat. NH₄Cl(20 mL), then the mixture was extracted with EtOAc (50 mL×2). Thecombined organic phase was washed with water (30 mL) and brine (30 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product(2300 mg, 7.99 mmol) as oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.99 (d, 1H),7.56 (dd, 1H), 5.82-5.69 (m, 1H), 1.54 (d, 3H).

A mixture of5-bromo-3-fluoro-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine (2.3g, 7.99 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(6.08 g, 23.96 mmol), KOAc (1.57 g, 15.97 mmol) and Pd(dppf)Cl₂ (876.39mg, 1.2 mmol) in 1,4-Dioxane (60 mL) was stirred at 85° C. for 12 hoursunder N₂. After cooling to r.t., the mixture was concentrated to givethe residue. The residue was diluted with H₂O (30 mL), and the mixturewas extracted with EtOAc (50 mL×2). The combined organic phase waswashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 2%) togive the product (4200 mg, 12.53 mmol) as an oil. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.25 (d, 1H), 7.70 (dd, 1H), 5.95-5.82 (m, 1H), 1.54 (d,3H), 1.34 (s, 12H).

A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (2 g, 10.25 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(3.09 g, 9.23 mmol), Pd(dppf)Cl₂ (1.13 g, 1.54 mmol) and K₂CO₃ (2.83 g,20.51 mmol) in 1,4-Dioxane (80 mL) and Water (20 mL) was stirred at 70°C. for 3 hours under N₂. After cooling to r.t., the mixture wasconcentrated to the residue. The residue was diluted with H₂O (50 mL),and the mixture was extracted with EtOAc (100 mL×2). The combinedorganic phase was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 5% to 10%) to give the product (3400 mg, 5.01 mmol) as anoil. LCMS R_(t)=0.99 min in 1.5 min chromatography, MS ESI calcd. forC₁₃H₁₁ClF₄N₃OS [M+H]⁺ 368.0, found 367.9.

A mixture of4-chloro-6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidine(3.4 g, 9.25 mmol), dicyanozinc (2.17 g, 18.49 mmol), Zn (90.68 mg, 1.39mmol), Pd₂(dba)₃ (846.62 mg, 0.92 mmol) and dppf (1.28 g, 2.31 mmol) inDMF (50 mL) was stirred at 90° C. for 2 hours under N₂. After cooling tor.t., the mixture was diluted with H₂O (80 mL), and the mixture wasextracted with EtOAc (150 mL×2). The combined organic phase was washedwith water (50 mL×2) and brine (50 mL), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 5% to 10%) togive the product (2400 mg, 3.55 mmol) as an oil. LCMS R_(t)=0.97 min in1.5 min chromatography, MS ESI calcd. for C₁₄H₁₁F₄N₄OS [M+H]⁺ 359.1,found 358.9.

To a mixture of6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidine-4-carbonitrile(2.6 g, 7.26 mmol) and NiCl₂.6H₂O (2.59 g, 10.88 mmol) in Methanol (30mL) was added NaBH₄ (686.26 mg, 18.14 mmol) at 10° C., then the mixturewas stirred at 25° C. for 0.5 hour. The mixture was quenched by H₂O (50mL), and the mixture was extracted with EtOAc (150 mL×2). The combinedorganic phase was washed with water (50 mL) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product (2400mg, 0.98 mmol) as an oil. LCMS R_(t)=0.77 min in 1.5 min chromatography,MS ESI calcd. for C₁₄H₁₅F₄N₄OS [M+H]⁺ 363.1, found 362.9.

A mixture of[6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methanamine(2.4 g, 6.62 mmol) in formic acid (50 g, 1086.3 mmol) was stirred at105° C. for 12 hours. After cooling to r.t., the mixture wasconcentrated to give the crude product (2400 mg, 6.15 mmol) as an oil,the crude product was used next step without further purification. LCMSR_(t)=0.85 min in 1.5 min chromatography, MS ESI calcd. forC₁₅H₁₅F₄N₄O₂S [M+H]⁺ 391.1, found 390.9.

To a mixture ofN-[[6-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methyl]formamide(2.4 g, 6.15 mmol) in 1,4-Dioxane (50 mL) was added POCl₃ (1.15 mL, 12.3mmol), then the mixture was stirred at 90° C. for 1 hour. After coolingto r.t., the mixture was poured into ice-water (100 mL) and the mixturewas basified with Na₂CO₃ (solid) to pH˜9, and extracted with EtOAc (150mL×2). The combined organic phase was washed with water (50 mL×2) andbrine (50 mL), dried over Na₂SO₄, filtered and concentrated to give thecrude product. The crude product was purified by flash chromatography onsilica gel (EtOAc in PE=0% to 30% to 60%) to give the product (270 mg,0.45 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.59 (d, 1H), 8.19(s, 1H), 8.03 (dd, 1H), 7.57-7.45 (m, 2H), 5.97-5.83 (m, 1H), 2.87 (s,3H), 1.59 (d, 3H). LCMS R_(t)=0.88 min in 1.5 min chromatography, MS ESIcalcd. for C₁₅H₁₃F₄N₄OS [M+H]⁺ 373.1, found 372.9.

To a mixture of7-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-5-methylsulfanyl-imidazo[1,5-c]pyrimidine(270 mg, 0.73 mmol) and 10% Pd/C (250 mg) in THE (20 mL) was addedEt₃SiH (7 g, 60.2 mmol) at 15° C., then the mixture was stirred at 15°C. for 2 hours. The mixture was filtered through Celite, and thefiltrate was concentrated to the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 50% to100%) to give the product (90 mg, 0.16 mmol) as a solid.

LCMS R_(t)=1.88 min in 3.0 min chromatography, MS ESI calcd. forC₁₄H₁₁F₄N₄O [M+H]⁺ 327.1, found 327.1.

The impure7-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]imidazo[1,5-c]pyrimidine(15 mg, 30.0 μmol) was purified by Prep-TLC (silica gel, PE:EtOAc=1:2)to give the product (4.95 mg, 15.2 μmol, 57% yield) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H)=8.94 (s, 1H), 8.52 (d, 1H), 8.29 (s, 1H), 8.03(dd, 1H), 7.67 (s, 1H), 7.53 (s, 1H), 5.94-5.83 (m, 1H), 1.59 (d, 3H).LCMS R_(t)=1.88 min in 3.0 min chromatography, MS ESI calcd. forC₁₄H₁₁F₄N₄ [M+H]⁺ 327.1, found 327.1.

Example 13: Synthesis of Compound 13

To a solution of 1,1,1-trifluoro-2-methyl-propan-2-ol (3 g, 23.42 mmol)in THF (10 mL) was added NaH (936.84 mg, 23.42 mmol). Then to themixture was added 5-bromo-2,3-difluoro-pyridine (4.54 g, 23.42 mmol),and the mixture was stirred at 80° C. for 16 hours. After cooling tor.t., the mixture was diluted with H₂O (10 mL) and extracted with EtOAc(10 mL×2). The combined organic phase was washed with brine (10 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 2%) to give the product (2800 mg, 9.27 mmol) as acolorless oil. ¹H NMR (400 MHz, CDCl₃) δ_(H)=7.99 (d, 1H), 7.54 (dd,1H), 1.80 (d, 6H).

A mixture of5-bromo-3-fluoro-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine (1.5 g,4.97 mmol),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(1.89 g, 7.45 mmol), Pd(dppf)Cl₂ (545.03 mg, 0.74 mmol) and KOAc (974.71mg, 9.93 mmol) in 1,4-Dioxane (20 mL) was stirred at 90° C. for 16 hoursto give a brown mixture. After cooling to r.t., the suspension wasdiluted with EtOAc (10 mL), filtered through silica gel, eluted withEtOAc (20 mL). The filtrate was concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=0% to 10%) to give the product (1000 mg, 2.86 mmol) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.26 (d, 1H), 7.67 (dd, 1H), 1.83(s, 6H), 1.34 (s, 12H).

A mixture of 4,6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.63 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(8.05 g, 23.07 mmol), K₂CO₃ (7.09 g, 51.26 mmol) and Pd(dppf)Cl₂ (2.81g, 3.84 mmol) in 1,4-Dioxane (200 mL) and Water (50 mL) was stirred at70° C. under N₂ for 12 hours to give a black suspension. After coolingto r.t., the mixture was concentrated to give a residue. To the residuewas added water (100 mL), extracted with EtOAc (100 mL×2). The combinedorganic phase was washed with brine (100 mL×2), dried over anhydrousNa₂SO₄, filtered and concentrated to give the crude product. The crudeproduct was purified by flash chromatography column on silica gel (EtOAcin PE=0% to 10% to 20%) to give the product of (8 g, 11.27 mmol) as asolid. LCMS R_(t)=1.02 min in 1.5 min chromatography, MS ESI calcd. forC₁₄H₁₃ClF₄N₃OS [M+H]⁺ 382.0, found 381.9.

A mixture of4-chloro-6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidine(8 g, 20.95 mmol), dicyanozinc (4.92 g, 41.91 mmol), dppf (2.90 g, 5.24mmol), Zn (205.53 mg, 3.14 mmol) and Pd₂(dba)₃ (1.91 g, 2.1 mmol) in DMF(50 mL) was stirred at 90° C. under N₂ for 2 hours to give a blackmixture. After cooling to r.t., the mixture was diluted with H₂O (80mL), and the mixture was extracted with EtOAc (150 mL×2). The combinedorganic phase was washed with water (50 mL×2) and brine (50 mL), driedover Na₂SO₄, filtered and concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=0% to 5% to 10%) to give the product (4.5 g, 7.72 mmol) as asolid. LCMS R_(t)=1.25 min in 2.0 min chromatography, MS ESI calcd. forC₁₅H₁₃F₄N₄OS [M+H]⁺ 373.1, found 373.0.

To a mixture of6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidine-4-carbonitrile(4.5 g, 12.09 mmol) and NiCl₂.6H₂O (4.3 g, 18.13 mmol) in Methanol (60mL) was added NaBH₄ (1.14 g, 30.21 mmol). The resulting mixture wasstirred at 0° C. for 0.5 hour to give a black mixture. To the mixturewas added water (40 mL) and EtOAc (80 mL) and then filtered throughCelite. After separation, the organic phase was washed with water (20mL×2), brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product (4.5 g) as an oil which was usedto next step directly. LCMS R_(t)=0.97 min in 2.0 min chromatography, MSESI calcd. for C₁₅H₁₇F₄N₄OS [M+H]⁺ 377.1, found 377.0.

A solution of[6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methanamine(4.5 g, 11.96 mmol) in formic acid (20 mL, 11.96 mmol) was stirred at105° C. for 12 hours to give a solution. The solution was cooled to roomtemperature and concentrated to give the crude product (4.0 g) as an oilwhich was used to next step directly. LCMS R_(t)=0.88 min in 1.5 minchromatography, MS ESI calcd. for C₁₆H₁₇F₄N₄O₂S [M+H]⁺ 405.1, found405.0.

A mixture ofN-[[6-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-2-methylsulfanyl-pyrimidin-4-yl]methyl]formamide(4.0 g, 9.89 mmol) and POCl₃ (1.84 mL, 19.78 mmol) in 1,4-Dioxane (100mL) was stirred at 90° C. for 2 hours to give a mixture. The mixture wascooled to room temperature and poured into ice-water (100 mL), adjustingthe pH to 9 with solid Na₂CO₃. The resulting mixture was extracted withEtOAc (100 mL×2). The combined organic phase was washed with water (50mL×2), brine (50 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography column on silica gel (EtOAc in PE=0% to 15% to30%) to give the product (570 mg, 1.18 mmol) as a solid. LCMS R_(t)=0.92min in 1.5 min chromatography, MS ESI calcd. for C₁₆H₁₅F₄N₄OS [M+H]⁺387.1, found 387.0.

To a mixture of7-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-5-methylsulfanyl-imidazo[1,5-c]pyrimidine(570 mg, 1.48 mmol) and Pd/C (335 mg, 1.48 mmol) in THE (20 mL) wasadded Et₃SiH (2 mL, 118.02 mmol). The mixture was stirred at 20° C. for1 hour to give a black mixture. The mixture was filtered through Celiteand concentrated to give the crude product. The crude product waspurified by flash chromatography column on silica gel (EtOAc in PE=0% to50% to 100%) to give the impure product (70 mg). The impure product (20mg) was purified by Prep-TLC (PE:EtOAc=1:3) to give the product (8.28mg, 24.1 μmol, 41% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.95(s, 1H), 8.53 (d, 1H), 8.29 (s, 1H), 7.99 (dd, 1H), 7.67 (s, 1H), 7.53(s, 1H), 1.86 (s, 6H). LCMS R_(t)=1.94 min in 3.0 min chromatography, MSESI calcd. for C₁₅H₁₃F₄N₄₀ [M+H]⁺ 341.1, found 341.1.

Example 14: Synthesis of Compound 14

A mixture of7-[2-methyl-4-(trifluoromethoxy)phenyl]imidazo[1,5-c]pyrimidine (240 mg,0.67 mmol) in DMF (10 mL) was added a solution of NIS (150 mg, 0.67mmol) in DMF (5 mL), then the mixture was stirred at 15° C. for 2 hours.The mixture was diluted with H₂O (20 mL), and the mixture was extractedwith EtOAc (50 mL×2). The combined organic phase was washed with water(20 mL×2) and brine (20 mL×2), dried over Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography on silica gel (EtOAc in PE=0% to 20% to 50%) togive the product (280 mg, 0.63 mmol, 94% yield) as a solid. LCMSR_(t)=2.07 min in 3 min chromatography, MS ESI calcd. for C₁₄H₁₀F₃IN₃O[M+H]⁺ 420.0, found 419.9.

To a mixture of fluorosilver (552 mg, 4.35 mmol) in DMF (30 mL) wasadded trimethyl(trifluoromethyl)silane (805 mg, 5.66 mmol) under N₂ at15° C., then the mixture was stirred at 15° C. for 3 hours. To themixture was added copper (443 mg, 6.97 mmol), then the mixture wasstirred at 15° C. for 16 hours under N₂. Trifluoromethylcopper (576 mg,4.35 mmol) was obtained as a solution in DMF (0.145 M, 30 mL), which wasused next step directly.

A mixture of1-iodo-7-[2-methyl-4-(trifluoromethoxy)phenyl]imidazo[1,5-c]pyrimidine(70 mg, 0.17 mmol) in CuCF₃/DMF (10 mL, 1.45 mmol) was stirred at 20° C.for 1 hour and 90° C. for 12 hours in a 20 mL sealed tube under N₂.After cooling to r.t., the mixture was diluted with H₂O (20 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=2:1) to give the product(21.37 mg, 57.7 μmol, 35% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.02 (s, 1H), 8.33 (s, 1H), 7.58 (s, 1H), 7.51 (d, 1H), 7.21-7.14(m, 2H), 2.47 (s, 3H). LCMS R_(t)=2.09 min in 3.0 min chromatography, MSESI calcd. for C₁₅H₁₀F₆N₃O [M+H]⁺ 362.1, found 362.0.

Example 15: Synthesis of Compound 15

A mixture of7-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]imidazo[1,5-c]pyrimidine(75 mg, 0.23 mmol) in DMF (5 mL) was added a solution of NIS (52 mg,0.23 mmol) in DMF (2 mL), then the mixture was stirred at 15° C. for 2hours. The mixture was diluted with H₂O (10 mL), and the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith water (15 mL×2) and brine (15 mL×2), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to60%) to give the product (75 mg, 0.16 mmol, 67% yield) as a solid. LCMSR_(t)=0.95 min in 1.5 min chromatography, MS ESI calcd. for C₁₄H₁₀F₄IN₄O[M+H]⁺ 453.0, found 452.9.

To a mixture of fluorosilver (552 mg, 4.35 mmol) in DMF (30 mL) wasadded trimethyl(trifluoromethyl)silane (805 mg, 5.66 mmol) under N₂ at15° C., then the mixture was stirred at 15° C. for 3 hours. To themixture was added copper (443 mg, 6.97 mmol), then the mixture wasstirred at 15° C. for 16 hours under N₂. Trifluoromethylcopper (576 mg,4.35 mmol, 100% yield) was obtained as a solution in DMF (0.145 M, 30mL), which was used next step directly.

A mixture of7-[5-fluoro-6-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-1-iodo-imidazo[1,5-c]pyrimidine(25 mg, 0.06 mmol) in CuCF₃/DMF (3.5 mL, 0.51 mmol) was stirred at 20°C. for 1 hour and 90° C. for 12 hours in a 10 m L sealed tube under N₂.After cooling to r.t., the mixture was diluted with H₂O (20 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=2:1) to give the product(5.36 mg, 13.4 μmol, 24% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.01 (d, 1H), 8.60 (d, 1H), 8.31 (s, 1H), 8.07 (dd, 1H), 7.81 (s,1H), 5.96-5.85 (m, 1H), 1.59 (d, 3H). LCMS R_(t)=3.60 min in 7.0 minchromatography, MS ESI calcd. for C₁₅H₁₀F₇N₄O [M+H]⁺ 395.1, found 395.0.

Example 16: Synthesis of Compound 16

A mixture of7-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]imidazo[1,5-c]pyrimidine(130 mg, 0.42 mmol) in DMF (6 mL) was added a solution of NIS (93.06 mg,0.41 mmol) in DMF (3 mL), then the mixture was stirred at 15° C. for 2hours. The mixture was diluted with H₂O (10 mL), and the mixture wasextracted with EtOAc (30 mL×2). The combined organic phase was washedwith water (15 mL×2) and brine (15 mL×2), dried over Na₂SO₄, filteredand concentrated to give the crude product. The crude product waspurified by flash chromatography on silica gel (EtOAc in PE=0% to 30% to60%) to give the product (130 mg, 0.27 mmol, 66% yield) as a solid. LCMSR_(t)=0.91 min in 1.5 min chromatography, MS ESI calcd. for C₁₃H₈F₄IN₄O[M+H]⁺ 439.0, found 438.8.

To a mixture of fluorosilver (552 mg, 4.35 mmol) in DMF (30 mL) wasadded trimethyl(trifluoromethyl)silane (805 mg, 5.66 mmol) under N₂ at15° C., then the mixture was stirred at 15° C. for 3 hours. To themixture was added copper (443 mg, 6.97 mmol), then the mixture wasstirred at 15° C. for 16 hours under N₂. Trifluoromethylcopper (576 mg,4.35 mmol, 100% yield) was obtained as a solution in DMF (0.15 M, 30mL), which was used next step directly.

A mixture of7-[5-fluoro-6-(2,2,2-trifluoroethoxy)-3-pyridyl]-1-iodo-imidazo[1,5-c]pyrimidine(45 mg, 0.10 mmol) in CuCF₃/DMF (6 mL, 0.87 mmol) was stirred at 20° C.for 1 hour and 90° C. for 12 hours in a 20 m L sealed tube under N₂.After cooling to r.t., the mixture was diluted with H₂O (20 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=2:1) to give the product(9.98 mg, 26.2 μmol, 26% yield) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=9.02 (s, 1H), 8.61 (d, 1H), 8.32 (s, 1H), 8.09 (dd, 1H), 7.82 (s,1H), 4.92 (q, 2H). LCMS R_(t)=1.03 min in 2.0 min chromatography, MS ESIcalcd. for C₁₄H₈F₇N₄ [M+H]⁺ 381.1, found 380.8.

Example 17: Synthesis of Compound 17

To a solution of7-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]imidazo[1,5-c]pyrimidine(30 mg, 0.09 mmol) in DMF (2 mL) was added NIS (27.58 mg, 0.12 mmol) inDMF (0.5 mL). The resulting solution was stirred at 20° C. for 1 hour.To the solution was added water (15 mL), and extracted with EtOAc (20mL×2). The combined organic phase was washed with water (20 mL), brine(20 mL×2), dried over anhydrous Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by flashchromatography column on silica gel (EtOAc in PE=0% to 20% to 50%) togive the product (10 mg, 21.5 μmol, 24% yield) as a solid which was usedinto next step directly. LCMS R_(t)=1.34 min in 2.0 min chromatography,MS ESI calcd. for C₁₅H₁₂F₄IN₄O [M+H]⁺ 467.0, found 466.8.

To a mixture of fluorosilver (552 mg, 4.35 mmol) in DMF (30 mL) wasadded trimethyl(trifluoromethyl)silane (805 mg, 5.66 mmol) under N₂ at15° C., then the mixture was stirred at 15° C. for 3 hours. To themixture was added copper (443 mg, 6.97 mmol), then the mixture wasstirred at 15° C. for 16 hours under N₂. Trifluoromethylcopper (576 mg,4.35 mmol, 100% yield) was obtained as a solution in DMF (0.145 M, 30mL), which was used next step directly.

A mixture of7-[5-fluoro-6-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)-3-pyridyl]-1-iodo-imidazo[1,5-c]pyrimidine(10 mg, 0.02 mmol) in CuCF₃/DMF (2.5 mL, 0.36 mmol) was stirred at 20°C. for 1 hour and 90° C. for 12 hours in a 10 mL sealed tube under N₂.After cooling to r.t., the mixture was diluted with H₂O (20 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product(1.93 mg, 4.7 μmol, 22% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) 400MHz δ_(H)=9.01 (d, 1H), 8.60 (d, 1H), 8.31 (s, 1H), 8.04 (dd, 1H), 7.81(s, 1H), 1.88 (s, 6H). LCMS R_(t)=3.91 min in 7.0 min chromatography, MSESI calcd. for C₁₆H₁₂F₇N₄O [M+H]⁺ 409.1, found 409.1.

Example 18: Synthesis of Compound 18

To a solution of7-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]imidazo[1,5-c]pyrimidine(40 mg, 0.12 mmol) in DMF (2 mL) was added NIS (27.58 mg, 0.12 mmol) inDMF (0.50 mL). The resulting solution was stirred at 20° C. for 1 hourto give a solution. To the solution was added water (15 mL), extractedwith EtOAc (20 mL×2). The combined organic phase was washed with water(20 mL), brine (20 mL×2), dried over anhydrous Na₂SO₄, filtered andconcentrated to give the crude product. The crude product was purifiedby flash chromatography column on silica gel (EtOAc in PE=0% to 20% to50%) to give the product (25 mg, 55.3 μmol, 45% yield) as a solid whichwas used into next step directly. LCMS R_(t)=1.29 min in 2.0 minchromatography, MS ESI calcd. for C₁₄H₁₀F₄IN₄O [M+H]⁺ 453.0, found452.8.

To a mixture of fluorosilver (552 mg, 4.35 mmol) in DMF (30 mL) wasadded trimethyl(trifluoromethyl)silane (805 mg, 5.66 mmol) under N₂ at15° C., then the mixture was stirred at 15° C. for 3 hours. To themixture was added copper (443 mg, 6.97 mmol), then the mixture wasstirred at 15° C. for 16 hours under N₂. Trifluoromethylcopper (576 mg,4.35 mmol, 100% yield) was obtained as a solution in DMF (0.145 M, 30mL), which was used next step directly.

A mixture of7-[5-fluoro-6-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]-3-pyridyl]-1-iodo-imidazo[1,5-c]pyrimidine(25 mg, 0.06 mmol) in CuCF₃/DMF (3.5 mL, 0.51 mmol) was stirred at 20°C. for 1 hours and 90° C. for 12 hours in a 10 mL sealed tube under N₂.After cooling to r.t., the mixture was diluted with H₂O (20 mL), and themixture was extracted with EtOAc (50 mL×2). The combined organic phasewas washed with water (20 mL×2) and brine (20 mL), dried over Na₂SO₄,filtered and concentrated to give the crude product. The crude productwas purified by Prep-TLC (silica gel, PE:EtOAc=1:1) to give the product(5.64 mg, 14.3 mmol, 26% yield) as a solid. ¹H NMR (400 MHz, CDCl₃) 400MHz δ_(H)=9.01 (d, 1H), 8.60 (d, 1H), 8.31 (s, 1H), 8.07 (dd, 1H), 7.81(s, 1H), 5.93-5.87 (m, 1H), 1.59 (d, 3H). LCMS R_(t)=3.58 min in 7.0 minchromatography, MS ESI calcd. for C₁₅H₁₀F₇N₄O [M+H]⁺ 395.1, found 395.1.

Example 19: Synthesis of Compound 19

To a solution of ethyl 2-isocyanoacetate (33.61 mL, 307.58 mmol) in DMSO(500 mL) was added DBU (45.95 mL, 307.58 mmol) at 10° C., followed by4,6-dichloro-2-methylsulfanyl-pyrimidine (60 g, 307.58 mmol), and thesuspension was stirred at 10° C. for 16 hours. The mixture was pouredinto water (300 mL), and the mixture was diluted with EtOAc (150 mL),filtered through Celite and eluted with EtOAc (100 mL×2). The filtratewas separated, and the aqueous phase was extracted with EtOAc (300 mL).The combined organic phase was washed with H₂O (100 mL) and brine (100mL), dried over Na₂SO₄, filtered through silica gel, eluted with EtOAc(100 mL×2) and concentrated to give the crude product. The crude productwas purified by flash chromatography on silica gel (EtOAc in PE=20% to40% to 70% to 100%) to give the impure product, which was trituratedfrom EtOAc (20 mL) to give the product (4600 mg, 16.93 mmol, 6% yield)as a solid. The mother liquid was purified by flash chromatography onsilica gel (EtOAc in PE=20% to 40% to 70% to 100%) to give another batchof the impure product, which was triturated from EtOAc (10 mL) to givethe product (2600 mg, 9.57 mmol, 3% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.12 (s, 1H), 7.80 (s, 1H), 4.47 (q, 2H), 2.83 (s, 3H),1.46 (t, 3H).

To a solution of ethyl7-chloro-5-methylsulfanyl-imidazo[1,5-c]pyrimidine-1-carboxylate (4 g,14.72 mmol) in THF (150 mL) was added DIBAL-H (36.8 mL, 36.8 mmol) at15° C., and the mixture was stirred at 15° C. for 1 hour. To the mixturewas added saturated solution of potassium sodium tartrate (˜100 mL) andEtOAc (100 mL), and the mixture was stirred at 15° C. for 1 hour. Afterseparation, the aqueous phase was extracted with EtOAc (100 mL×2). Thecombined organic phase was washed with brine (30 mL), dried over Na₂SO₄,filtered and concentrated to give the product (2900 mg, 12.63 mmol, 86%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.09 (s, 1H), 7.26 (s,1H), 4.89 (s, 2H), 2.80 (s, 3H), 2.43 (br s, 1H).

A mixture of(7-chloro-5-methylsulfanyl-imidazo[1,5-c]pyrimidin-1-yl)methanol (2.7 g,11.75 mmol) and MnO₂ (10.22 g, 117.55 mmol) in Chloroform (150 mL) wasstirred at 70° C. for 2 hours. The hot mixture was filtrated through theCelite and eluted with DCM (30 mL×2). The filtrate was concentrated togive the product (1500 mg, 6.56 mmol, 56% yield) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H)=10.10 (s, 1H), 8.13 (s, 1H), 7.91 (s, 1H), 2.85 (s,3H).

A mixture of7-chloro-5-methylsulfanyl-imidazo[1,5-c]pyrimidine-1-carbaldehyde (1.3g, 5.71 mmol) and DAST (15 mL, 113.53 mmol) was stirred at 10° C. for 12hours to give a suspension. To the mixture was added DCM (10 mL) andDAST (5 mL), and the mixture was stirred at 10° C. for another 6 hours.The mixture was added to ice water (˜50 mL) dropwise, and the mixturewas basified with NaHCO₃ (solid) to pH˜8. The mixture was extracted withEtOAc (50 mL×2), and the combined organic phase was washed with H₂O (30mL) and brine (30 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=20% to 40% to 50%) to give theproduct (280 mg, 1.12 mmol, 20% yield) as a solid. ¹H NMR (400 MHz,CDCl₃) δ_(H)=8.14 (s, 1H), 7.41 (s, 1H), 6.95 (t, 1H), 2.84 (s, 3H).LCMS R_(t)=0.86 min in 1.5 min chromatography, MS ESI calcd. forCH₇ClF₂N₃S [M+H]⁺ 250.0, found 249.9.

To a mixture of7-chloro-1-(difluoromethyl)-5-methylsulfanyl-imidazo[1,5-c]pyrimidine(280 mg, 1.12 mmol) in THE (10 mL) was added 10% Pd/C (600 mg) andEt₃SiH (6.46 g, 55.57 mmol), then the mixture was stirred at 20° C. for3 hours. The mixture was filtered through Celite, and the filtrate wasconcentrated to the crude product. The crude product was purified byflash chromatography on silica gel (EtOAc in PE=0% to 50% to 100%) togive the product (145 mg, 0.71 mmol, 64% yield) as a solid. ¹H NMR (400MHz, CDCl₃) δ_(H)=8.81 (d, 1H), 8.25 (s, 1H), 7.62 (s, 1H), 6.96 (t,1H).

A mixture of 7-chloro-1-(difluoromethyl)imidazo[1,5-c]pyrimidine (20 mg,0.10 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(65.84 mg, 0.20 mmol), Pd(t-Bu₃P)₂ (10.04 mg, 0.02 mmol) and K₃PO₄(41.71 mg, 0.20 mmol) in 1,4-Dioxane (2 mL) and Water (0.20 mL) wasstirred at 80° C. for 2 hours under N₂. After cooling to r.t., themixture was diluted with H₂O (5 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (5mL×2) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (13.27 mg, 34.6 μmol, 35%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.98 (d, 1H), 8.58 (d,1H), 8.27 (s, 1H), 8.06 (dd, 1H), 7.87 (s, 1H), 7.02 (t, 1H), 5.95-5.85(m, 1H), 1.59 (d, 3H). LCMS R_(t)=1.99 min in 3.0 min chromatography(mobile phase: 0.5 mL/1 L NH₃H₂O in water (solvent A) and acetonitrile(solvent B), using the elution gradient 10%-80% (solvent B) over 2minutes and holding at 80% for 0.48 minutes at a flow rate of 1.0ml/min; Column: Xbrige Shield RP-18.5 um, 2.1*50 mm; Wavelength: UV 220nm & 254 nm; Column temperature: 30° C.; MS ionization: ESI), MS ESIcalcd. for C₁₅H₁₁F₆N₄O [M+H]⁺ 377.1, found 377.0.

Example 20: Synthesis of Compound 20

A mixture of 7-chloro-1-(difluoromethyl)imidazo[1,5-c]pyrimidine (30 mg,0.15 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(74.07 mg, 0.22 mmol), Pd(t-Bu₃P)₂ (15.06 mg, 0.03 mmol) and K₃PO₄(62.57 mg, 0.29 mmol) in 1,4-Dioxane (3 mL) and Water (0.30 mL) wasstirred at 80° C. for 2 hours under N₂. After cooling to r.t., themixture was diluted with H₂O (5 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (5mL×2) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (26.24 mg, 69.5 μmol, 47%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.98 (d, 1H), 8.58 (d,1H), 8.26 (s, 1H), 8.06 (dd, 1H), 7.87 (s, 1H), 7.02 (t, 1H), 5.95-5.85(m, 1H), 1.59 (d, 3H). LCMS R_(t)=1.99 min in 3.0 min chromatography, MSESI calcd. for C₁₅H₁₁F₆N₄O [M+H]⁺ 377.1, found 377.0.

Example 21: Synthesis of Compound 21

A mixture of 7-chloro-1-(difluoromethyl)imidazo[1,5-c]pyrimidine (30 mg,0.15 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(154.35 mg, 0.44 mmol), Pd(t-Bu₃P)₂ (22.59 mg, 0.04 mmol) and K₃PO₄(62.57 mg, 0.29 mmol) in 1,4-Dioxane (3 mL) and Water (0.30 mL) wasstirred at 85° C. for 4 hours under N₂. After cooling to r.t., themixture was diluted with H₂O (5 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (5mL×2) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (16.11 mg, 41.1 μmol, 28%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.98 (d, 1H), 8.58 (d,1H), 8.26 (s, 1H), 8.03 (dd, 1H), 7.88 (s, 1H), 7.02 (t, 1H), 1.87 (s,6H). LCMS R_(t)=2.05 min in 3.0 min chromatography, MS ESI calcd. forC₁₆H₁₃F₆N₄O [M+H]⁺ 391.1, found 391.1.

Example 22: Synthesis of Compound 22

A mixture of 7-chloro-1-(difluoromethyl)imidazo[1,5-c]pyrimidine (30 mg,0.15 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoroethoxy)pyridine(236.58 mg, 0.74 mmol), Pd(t-Bu₃P)₂ (22.59 mg, 0.04 mmol) and K₃PO₄(62.57 mg, 0.29 mmol) 20 in 1,4-Dioxane (3 mL) and Water (0.30 mL) wasstirred at 85° C. for 3 hours under N₂. After cooling to r.t., themixture was diluted with H₂O (5 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (5mL×2) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (41.38 mg, 0.11 mmol, 76%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.98 (d, 1H), 8.59 (d,1H), 8.27 (s, 1H), 8.08 (dd, 1H), 7.88 (s, 1H), 7.02 (t, 1H), 4.91 (q,2H). LCMS R_(t)=1.91 min in 3.0 min chromatography, MS ESI calcd. forC₁₄H₉F₆N₄₀ [M+H]⁺ 363.1, found 363.0.

Example 23: Synthesis of Compound 23

A mixture of 7-chloro-1-(difluoromethyl)imidazo[1,5-c]pyrimidine (30 mg,0.15 mmol),4,4,5,5-tetramethyl-2-[2-methyl-4-(trifluoromethoxy)phenyl]-1,3,2-dioxaborolane(178.07 mg, 0.59 mmol), Pd(t-Bu₃P)₂ (22.59 mg, 0.04 mmol) and K₃PO₄(62.57 mg, 0.29 mmol) in 1,4-Dioxane (2 mL) and Water (0.30 mL) wasstirred at 85° C. for 7 hours under N₂. After cooling to r.t., themixture was diluted with H₂O (5 mL), and the mixture was extracted withEtOAc (20 mL×2). The combined organic phase was washed with water (5mL×2) and brine (5 mL), dried over Na₂SO₄, filtered and concentrated togive the crude product. The crude product was purified by Prep-TLC(silica gel, PE:EtOAc=2:1) to give the product (1.88 mg, 5.5 μmol, 4%yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.99 (d, 1H), 8.28 (s,1H), 7.63 (s, 1H), 7.50 (d, 1H), 7.20-6.84 (m, 3H), 2.47 (s, 3H). LCMSR_(t)=3.01 min in 7.0 min chromatography (mobile Phase: 0.5 mL/1 LNH₃H₂O in water (solvent A) and acetonitrile (solvent B), using theelution gradient 30%-90% (solvent B) over 6 minutes and holding at 90%for 0.5 minutes at a flow rate of 0.8 ml/min; Column: Xbrige ShieldRP-18.5 um, 2.1*50 mm; Wavelength: UV 220 nm & 254 nm; Columntemperature: 30° C.; MS ionization: ESI), MS ESI calcd. for C₁₅H₁₁F₅N₃O[M+H]⁺ 344.1, found 344.1.

Example 24: Synthesis of Compound 24

A mixture of 7-chloro-1-(methoxymethyl)imidazo[1,5-c]pyrimidine (50 mg,0.25 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1S)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(101.74 mg, 0.30 mmol), K₃PO₄ (107.43 mg, 0.51 mmol) and Pd(t-Bu₃P)₂(19.4 mg, 0.04 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was stirredat 80° C. under N₂ for 5 hours to give a brown mixture. The reactionmixture was cooled to room temperature and filtered through Celite. Thefiltrate was concentrated to give a residue. To the residue was addedwater (10 mL), extracted with EtOAc (20 mL×2). The combined organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-HPLC (BostonPrime C18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B═CH₃CN; 50-80% Bover 9 minutes) to give the product (18.21 mg, 48.2 μmol) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H)=8.90 (s, 1H), 8.54 (d, 1H), 8.24 (s, 1H),8.03 (dd, 1H), 7.75 (s, 1H), 5.95-5.83 (m, 1H), 4.80 (s, 2H), 3.49 (s,3H), 1.58 (d, 3H). LCMS R_(t)=1.87 min in 3.0 min chromatography, MS ESIcalcd. for C₁₆H₁₅F₄N₄O₂ [M+H]⁺ 371.1, found 371.1.

Example 25: Synthesis of Compound 25

A mixture of 7-chloro-1-(methoxymethyl)imidazo[1,5-c]pyrimidine (50 mg,0.25 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-[(1R)-2,2,2-trifluoro-1-methyl-ethoxy]pyridine(101.74 mg, 0.30 mmol), K₃PO₄ (107.43 mg, 0.51 mmol) and Pd(t-Bu₃P)₂(19.4 mg, 0.04 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was stirredat 80° C. under N₂ for 5 hours to give a brown mixture. The reactionmixture was cooled to room temperature and filtered through Celite. Thefiltrate was concentrated to give a residue. To the residue was addedwater (10 mL), extracted with EtOAc (20 mL×2). The combined organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-HPLC (BostonPrime C18 (150 mm×30 mm, 5 μm) A=H₂O (0.05% NH₄OH) and B═CH₃CN; 50-80% Bover 9 minutes) to give the product (20.53 mg, 55.3 μmol) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H)=8.89 (s, 1H), 8.54 (d, 1H), 8.24 (s, 1H),8.03 (dd, 1H), 7.75 (s, 1H), 5.95-5.83 (m, 1H), 4.80 (s, 2H), 3.49 (s,3H), 1.58 (d, 3H). LCMS R_(t)=1.87 min in 3.0 min chromatography, MS ESIcalcd. for C₁₆H₁₅F₄N₄O₂ [M+H]⁺ 371.1, found 371.1.

Example 26: Synthesis of Compound 26

To a suspension of(7-chloro-5-methylsulfanyl-imidazo[1,5-c]pyrimidin-1-yl)methanol (2000mg, 8.71 mmol) in DCM (15 mL) was added MsCl (1.77 mL, 11.32 mmol) at 0°C., followed by Et₃N (1.45 mL, 10.45 mmol) drop wise, and the resultedyellow solution was stirred at 0° C. for 30 mins. The mixture wasconcentrated and the residue was dissolved in MeOH (50 mL), and themixture was stirred at 15° C. for 16 hours. The mixture was diluted withDCM (150 mL), and washed with sat.Na₂CO₃ (30 mL) and brine (30 mL). Theorganic phase was dried over Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by flashchromatography on silica gel (EtOAc in PE=40% to 60% to 100%) to givethe product (900 mg, 3.69 mmol) as a solid. ¹H NMR (400 MHz, CDCl₃)δ_(H)=8.09 (s, 1H), 7.25 (s, 1H), 4.69 (s, 2H), 3.43 (s, 3H), 2.79 (s,3H).

To a mixture of7-chloro-1-(methoxymethyl)-5-methylsulfanyl-imidazo[1,5-c]pyrimidine(900 mg, 3.69 mmol) and Pd/C (600 mg) in THE (20 mL) was added Et₃SiH(11.8 mL, 73.86 mmol), and the black mixture was stirred at 15° C. for 3hours. The mixture was filtered through Celite and eluted with EtOAc (30mL×2). The filtrate was concentrated to give the crude product. Thecrude product was purified by flash chromatography on silica gel (EtOAcin PE=40% to 60% to 100%) to give the product (530 mg, 2.68 mmol) as asolid. ¹H NMR (400 MHz, CDCl₃) δ_(H)=8.71 (d, 1H), 8.20 (s, 1H), 7.48(d, 1H), 4.71 (s, 2H), 3.45 (s, 3H).

A mixture of 7-chloro-1-(methoxymethyl)imidazo[1,5-c]pyrimidine (80 mg,0.40 mmol), [4-(trifluoromethoxy)phenyl]boronic acid (333.46 mg, 1.62mmol), K₃PO₄ (343.77 mg, 1.62 mmol) and Pd(t-Bu₃P)₂ (103.44 mg, 0.20mmol) in 1,4-Dioxane (3 mL) and Water (0.30 mL) was stirred at 80° C.for 5 hours. After cooling to r.t., the mixture was diluted with EtOAc(40 mL), and the mixture was washed with H₂O (10 mL) and brine (10 mL),dried over Na₂SO₄, filtered and concentrated to give the crude product.The crude product was purified by flash chromatography on silica gel(EtOAc in PE=20% to 40% to 60% to 100%) to give the impure product (˜30mg) as a solid. The impure product was purified by Prep-HPLC (BostonPrime C18 150×30 mm, 5 μm, A=H₂O (0.05% NH₄OH) and B═CH₃CN; 48-78% Bover 8 minutes) to give the product (13.42 mg, 41.5 μmol) as a solid. ¹HNMR (400 MHz, CDCl₃) δ_(H)=8.91 (d, 1H), 8.23 (s, 1H), 8.04 (d, 2H),7.80 (d, 1H), 7.32 (d, 2H), 4.80 (s, 2H), 3.48 (s, 3H). LCMS R_(t)=1.82min in 3.0 min chromatography, MS ESI calcd. for C₁₅H₁₃F₃N₃O₂ [M+H]⁺324.1, found 324.1.

Example 27: Synthesis of Compound 27

A mixture of 7-chloro-1-(methoxymethyl)imidazo[1,5-c]pyrimidine (80 mg,0.40 mmol),3-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(2,2,2-trifluoro-1,1-dimethyl-ethoxy)pyridine(212 mg, 0.61 mmol), K₃PO₄ (171.89 mg, 0.81 mmol) and Pd(t-Bu₃P)₂ (20mg, 0.40 mmol) in 1,4-Dioxane (20 mL) and Water (2 mL) was stirred at80° C. under N₂ for 6 hours to give a brown mixture. The reactionmixture was cooled to room temperature and filtered through Celite. Thefiltrate was concentrated to give a residue. To the residue was addedwater (10 mL), extracted with EtOAc (20 mL×2). The combined organicphase was dried over anhydrous Na₂SO₄, filtered and concentrated to givethe crude product. The crude product was purified by Prep-HPLC (Bostonprime (150 mm×30 mm, 5 μm) A=H₂ (0.05% NH₄OH) and B=ACN; 50-80% B over 8minutes) to give the product (55.3 mg, 0.14 mmol) as a solid. ¹H NMR(400 MHz, CDCl₃) δ_(H)=8.90 (d, 1H), 8.55 (d, 1H), 8.23 (s, 1H), 8.00(dd, 1H), 7.75 (d, 1H), 4.79 (s, 2H), 3.48 (s, 3H), 1.86 (s, 6H). LCMSR_(t)=1.94 min in 3.0 min chromatography, MS ESI calcd. for C₁₇H₁₇F₄N₄O₂[M+H]⁺ 385.1, found 385.1.

Example 28: Efficacy of Exemplary Compounds in the Modulation of LateSodium Current (INaL)

Functional characterization of exemplary compounds to modulate INaLexpressed by the Nav1.6 voltage-gated sodium channel was accomplishedusing the PatchXpress™ high throughput electrophysiology platform(Molecular Devices, Sunnyvale, Calif.). HEK-293 cells expressingrecombinant, human Nav1.6 (hNav1.6) were grown in DMEM/high-glucoseDulbecco's modified, 10% FBS, 2 mM sodium pyruvate, 10 mM HEPES and 400μg/mL G418. Cells were grown to 50%-80% confluency prior to harvesting.Trypsinized cells were washed, allowed to recover for 1 hour and thenresuspended in extracellular recording solution at a concentration of1×10⁶ cells/ml. The onboard liquid handling facility of the PatchXpresswas used for dispensing cells and applying test compounds. Nav latecurrents were evoked by the application of 300 nM ATX-II. INaL wasevoked by depolarizing pulses to 0 mV for 200 ms from a non-inactivatingholding potential (e.g., −120 mV) at a frequency of 0.1 Hz. INaLamplitude and stability were determined by analyzing the mean currentamplitude over the final 20 ms of the test pulse. Following steady stateblock with exemplary compounds (e.g., as described herein), a Na⁺ freesolution containing an impermeant cation (e.g., Choline or NDMG) wasadded to confirm the identify of the sodium current. Percentsteady-state inhibition of INaL was calculated as:[(INaL_compound)/(INaL_control)]*100, where INaL_compound andINaL_control represent INaL recorded in the presence or absence ofcompound, respectively.

Results from this assay relating to percent inhibition of INaL athNav1.6 (measured using procedure similar to described above but usingHEK-293 cells expressing recombinant, human Nav1.6 (hNav1.6) at 1 μM aresummarized in Table 1 below. In this table, “A” indicates inhibition ofless than 30%; “B” indicates inhibition of between about 30% to about70%; and “C” indicates inhibition of greater than 70%.

TABLE 1 INaL v1.6 Compound (1 μM, % Inhibition) 1 A 2 A 3 n/a 4 B 5 A 6A 7 A 8 C 9 A 10 A 11 B 12 A 13 B 14 C 15 B 16 A 17 B 18 B 19 A 20 A 21B 22 A 23 A 24 A 25 C 26 B 27 A

EQUIVALENTS AND SCOPE

In the claims articles such as “a,” “an,” and “the” may mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” between one or moremembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention includes embodiments in which more than one, or all of thegroup members are present in, employed in, or otherwise relevant to agiven product or process.

Furthermore, the invention encompasses all variations, combinations, andpermutations in which one or more limitations, elements, clauses, anddescriptive terms from one or more of the listed claims is introducedinto another claim. For example, any claim that is dependent on anotherclaim can be modified to include one or more limitations found in anyother claim that is dependent on the same base claim. Where elements arepresented as lists, e.g., in Markush group format, each subgroup of theelements is also disclosed, and any element(s) can be removed from thegroup. It should it be understood that, in general, where the invention,or aspects of the invention, is/are referred to as comprising particularelements and/or features, certain embodiments of the invention oraspects of the invention consist, or consist essentially of, suchelements and/or features. For purposes of simplicity, those embodimentshave not been specifically set forth in haec verba herein. It is alsonoted that the terms “comprising” and “containing” are intended to beopen and permits the inclusion of additional elements or steps. Whereranges are given, endpoints are included. Furthermore, unless otherwiseindicated or otherwise evident from the context and understanding of oneof ordinary skill in the art, values that are expressed as ranges canassume any specific value or sub-range within the stated ranges indifferent embodiments of the invention, to the tenth of the unit of thelower limit of the range, unless the context clearly dictates otherwise.

This application refers to various issued patents, published patentapplications, journal articles, and other publications, all of which areincorporated herein by reference. If there is a conflict between any ofthe incorporated references and the instant specification, thespecification shall control. In addition, any particular embodiment ofthe present invention that falls within the prior art may be explicitlyexcluded from any one or more of the claims. Because such embodimentsare deemed to be known to one of ordinary skill in the art, they may beexcluded even if the exclusion is not set forth explicitly herein. Anyparticular embodiment of the invention can be excluded from any claim,for any reason, whether or not related to the existence of prior art.

Those skilled in the art will recognize or be able to ascertain using nomore than routine experimentation many equivalents to the specificembodiments described herein. The scope of the present embodimentsdescribed herein is not intended to be limited to the above Description,but rather is as set forth in the appended claims. Those of ordinaryskill in the art will appreciate that various changes and modificationsto this description may be made without departing from the spirit orscope of the present invention, as defined in the following claims.

The invention claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein: wherein X and Zare both CH, and Y is N; A is phenyl or 5-6 membered heteroaryl, whereinphenyl and 5-6 membered heteroaryl are optionally substituted by one ormore R³; R¹ is independently selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, halo,and cyano, wherein C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 memberedheterocyclyl are optionally substituted with one or more R⁴; R² isselected from the group consisting of hydrogen, C₁₋₆ alkyl, halo, andcyano, wherein each C₁₋₆alkyl is optionally substituted with one or moreR⁴; each R³ is independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, halo, cyano,nitro, and —OR^(c), wherein C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10membered heterocyclyl are optionally substituted with one or more R⁵;each of R⁴ and R⁵ is independently selected from the group consisting ofC₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6membered heteroaryl, halo, cyano, nitro, and —OR^(c); each R^(c) isindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,phenyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, and 5-6 memberedheteroaryl, wherein C₁₋₆ alkyl, phenyl, or 5-6 membered heteroaryl isoptionally substituted by one or more R⁶; and each R⁶ is independentlyselected from the group consisting of C₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10membered heterocyclyl, halo, cyano, nitro, and —OH, wherein C₁₋₆ alkylis optionally substituted with one or more halo.
 2. The compound ofclaim 1, wherein A is phenyl.
 3. The compound of claim 1, wherein A isphenyl substituted by one R³.
 4. The compound of claim 1, wherein R³ is—OR^(c).
 5. The compound of claim 1, wherein R¹ is C₁₋₆alkyl substitutedwith 1-4 R⁴.
 6. The compound of claim 1, wherein the compound of Formula(I) is a compound of Formula (I-a):

or a pharmaceutically acceptable salt thereof, wherein: X and Z are bothCH, and Y is N; R¹ is selected from the group consisting of hydrogen,C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 membered heterocyclyl, whereinC₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 membered heterocyclyl areoptionally substituted with one or more R⁴; R² is hydrogen or C₁₋₆alkyl;each R³ is independently selected from the group consisting of C₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, halo, cyano, nitro,and —OR^(c), wherein C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 memberedheterocyclyl are optionally substituted with one or more R⁵; each of R⁴and R⁵ is independently selected from the group consisting of C₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 memberedheteroaryl, halo, cyano, nitro, and —OR^(c); each R^(c) is independentlyselected from the group consisting of hydrogen, C₁₋₆alkyl, phenyl,C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, and 5-6 memberedheteroaryl, wherein C₁₋₆ alkyl, phenyl, or 5-6 membered heteroaryl isoptionally substituted by one or more R⁶; each R⁶ is independentlyselected from the group consisting of C₁₋₆ alkyl, C₃₋₈carbocyclyl, 3-10membered heterocyclyl, halo, cyano, nitro, and —OH, wherein C₁₋₆ alkylis optionally substituted with one or more halo; and n is selected fromthe group consisting of 1, 2, 3, 4, and
 5. 7. The compound of claim 1,wherein the compound of Formula (I) is a compound of Formula (I-b):

or a pharmaceutically acceptable salt thereof, wherein: wherein X and Zare both CH, and Y is N; R¹ is selected from the group consisting ofhydrogen, C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 membered heterocyclyl,wherein C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 membered heterocyclyl areoptionally substituted with one or more R⁴; R² is hydrogen or C₁₋₆alkyl;each R³ is independently selected from the group consisting of C₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, halo, cyano, nitro,and —OR^(c), wherein C₁₋₆ alkyl, C₃₋₈carbocyclyl, and 3-10 memberedheterocyclyl are optionally substituted with one or more R⁵; each of R⁴and R⁵ is independently selected from the group consisting of C₁₋₆alkyl, C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, phenyl, 5-6 memberedheteroaryl, halo, cyano, nitro, and —OR^(c); each R^(c) is independentlyselected from the group consisting of hydrogen, C₁₋₆alkyl, phenyl,C₃₋₈carbocyclyl, 3-10 membered heterocyclyl, and 5-6 memberedheteroaryl, wherein C₁₋₆ alkyl, phenyl, or 5-6 membered heteroaryl isoptionally substituted by one or more R⁶; each R⁶ is independentlyselected from the group consisting of C₁₋₆ alkyl, C₃₋₈carbocyclyl, 3-10membered heterocyclyl, halo, cyano, nitro, and —OH, wherein C₁₋₆ alkylis optionally substituted with one or more halo; and m is selected fromthe group consisting of 0, 1, 2, and
 3. 8. The compound of claim 6,wherein R¹ is hydrogen or C₁₋₆alkyl optionally substituted with one ormore halogen.
 9. The compound of claim 6, wherein R¹ is selected fromthe group consisting of hydrogen, —CF₃, and —CHF₂.
 10. The compound ofclaim 6, wherein each R³ is selected from the group consisting of—OR^(c), C₁₋₆alkyl, and halo.
 11. The compound of claim 1, wherein thecompound of Formula (I) is a compound of formula (I-c):

or a pharmaceutically acceptable salt thereof, wherein: m is selectedfrom the group consisting of 0, 1, 2, 3, and 4, and R¹, X, Y, Z, R^(c),and R³ are as defined in claim
 6. 12. The compound of claim 1, whereinthe compound of Formula (I) is a compound of formula (I-k)

or a pharmaceutically acceptable salt thereof, wherein: p is selectedfrom the group consisting of 0, 1, 2, and 3, and R¹, R^(c), and R³ areas defined in claim
 7. 13. The compound of claim 1, wherein the compoundis selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.
 14. A pharmaceuticalcomposition comprising a compound of claim 1 or pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable carrier. 15.The compound of claim 7, wherein R¹ is C₁₋₆alkyl optionally substitutedwith one or more halogen or —OR^(c).
 16. The compound of claim 7,wherein each R³ is selected from the group consisting of —OR^(c),C₁₋₆alkyl, and halo.